|
1
|
Deng M, Huang P, Wang L, Jiang Y, Guo Z, Duan H, Zha J, Zhao H, Li G, Xu B. The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulation. Transl Oncol 2025; 57:102399. [PMID: 40373471 DOI: 10.1016/j.tranon.2025.102399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 11/25/2024] [Accepted: 04/15/2025] [Indexed: 05/17/2025] Open
Abstract
MLL gene rearrangement recurrently occurs in acute myeloid leukemia (MLL-r AML), which is closely associated with chemotherapy insensitivity and unfavorable clinical outcomes. More importantly, there are limited therapeutic options for the management of patients with MLL-r AML, thus necessitating novel effective treatment strategies. In this study, we demonstrated that low doses of triptolide (LD TPL) and the XPO1 inhibitor selinexor exerted synergistic therapeutic effects on poor-outcome MLL-r AML in vitro, ex vivo and in vivo. Induction of mitochondrial outer membrane permeabilization (MOMP) and initiation of the mitochondrial apoptotic pathway were closely involved in the therapeutic synergy of LD TPL in combination with selinexor against MLL-r AML. Mechanistically, MYC downregulation mediated by the Rap1/Raf/MEK/ERK pathway rather than by PI3K/AKT signaling was implicated in the synergistic activity of the combined regimen. In addition, the induction of DNA damage also contributed to the synergistic effects of the combined regimen on MLL-r AML. In summary, our findings suggest that LD TPL in combination with selinexor might represent a promising therapeutic approach for the treatment of MLL-r AML. However, future clinical trials are mandatory to draw a decisive conclusion.
Collapse
Affiliation(s)
- Manman Deng
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, China
| | - Peicui Huang
- Department of Hematology, Huizhou Municipal Central Hospital, Huizhou, 516001, PR China
| | - Lijuan Wang
- Department of Emergency, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Yuelong Jiang
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, China
| | - Zhenling Guo
- Department of Hematology, Huizhou Municipal Central Hospital, Huizhou, 516001, PR China
| | - Hongpeng Duan
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, China
| | - Jie Zha
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, China
| | - Haijun Zhao
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, China.
| | - Guowei Li
- Department of Hematology, Huizhou Municipal Central Hospital, Huizhou, 516001, PR China.
| | - Bing Xu
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, PR China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, China.
| |
Collapse
|
|
2
|
Wei Q, Hu S, Xu J, Loghavi S, Daver N, Toruner GA, Wang W, Medeiros LJ, Tang G. Detection of KMT2A Partial Tandem Duplication by Optical Genome Mapping in Myeloid Neoplasms: Associated Cytogenetics, Gene Mutations, Treatment Responses, and Patient Outcomes. Cancers (Basel) 2024; 16:4193. [PMID: 39766092 PMCID: PMC11674272 DOI: 10.3390/cancers16244193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/10/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
KMT2A partial tandem duplication (PTD) involves intragenic KMT2A duplications and has been associated with poorer prognosis. In this study, we evaluated KMT2A PTD in 1277 patients with hematological malignancies using optical genome mapping (OGM). KMT2A PTD was detected in 35 patients with acute myeloid leukemia (AML) (7%), 5 patients with myelodysplastic syndrome (MDS) (2.2%), and 5 patients with chronic myelomonocytic leukemia (CMML) (7.1%). The PTDs varied in size, region, and copy number. An Archer RNA fusion assay confirmed KMT2A PTD in all 25 patients tested: 15 spanning exons 2 to 8 and 10 spanning exons 2 to 10. Most patients exhibited a normal (n = 21) or non-complex (n = 20) karyotype. The most common chromosomal abnormalities included loss of 20q or 7q and trisomy 11/gain of 11q. All patients had gene mutations, with FLT3 ITD and DNMT3A prevalent in AML and DNMT3A and RUNX1 common in MDS and CMML. Among patients who received treatment and had at least one follow-up bone marrow evaluation, 82% of those with de novo AML achieved complete remission after initial induction chemotherapy, whereas 90% of patients with secondary or refractory/relapsed AML showed refractory or partial responses. All but one patient with MDS and CMML were refractory to therapy. We conclude that OGM is an effective tool for detecting KMT2A PTD. Neoplasms with KMT2A PTD frequently harbor gene mutations and display normal or non-complex karyotypes. Patients with KMT2A PTD are generally refractory to conventional therapy, except for de novo AML.
Collapse
Affiliation(s)
- Qing Wei
- Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; (Q.W.); (S.H.); (J.X.); (S.L.); (G.A.T.); (W.W.); (L.J.M.)
| | - Shimin Hu
- Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; (Q.W.); (S.H.); (J.X.); (S.L.); (G.A.T.); (W.W.); (L.J.M.)
| | - Jie Xu
- Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; (Q.W.); (S.H.); (J.X.); (S.L.); (G.A.T.); (W.W.); (L.J.M.)
| | - Sanam Loghavi
- Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; (Q.W.); (S.H.); (J.X.); (S.L.); (G.A.T.); (W.W.); (L.J.M.)
| | - Naval Daver
- Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA;
| | - Gokce A. Toruner
- Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; (Q.W.); (S.H.); (J.X.); (S.L.); (G.A.T.); (W.W.); (L.J.M.)
| | - Wei Wang
- Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; (Q.W.); (S.H.); (J.X.); (S.L.); (G.A.T.); (W.W.); (L.J.M.)
| | - L. Jeffrey Medeiros
- Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; (Q.W.); (S.H.); (J.X.); (S.L.); (G.A.T.); (W.W.); (L.J.M.)
| | - Guilin Tang
- Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA; (Q.W.); (S.H.); (J.X.); (S.L.); (G.A.T.); (W.W.); (L.J.M.)
| |
Collapse
|
|
3
|
Greiner J, Mohamed E, Fletcher DM, Schuler PJ, Schrezenmeier H, Götz M, Guinn BA. Immunotherapeutic Potential of Mutated NPM1 for the Treatment of Acute Myeloid Leukemia. Cancers (Basel) 2024; 16:3443. [PMID: 39456538 PMCID: PMC11505958 DOI: 10.3390/cancers16203443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/15/2024] [Accepted: 10/02/2024] [Indexed: 10/28/2024] Open
Abstract
Acute myeloid leukemia (AML) is a malignant disease of the blood and bone marrow that is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Nucleophosmin 1 (NPM1) gene mutations are the most common genetic abnormality in AML, detectable in blast cells from about one-third of adults with AML. AML NPM1mut is recognized as a separate entity in the World Health Organization classification of AML. Clinical and survival data suggest that patients with this form of AML often have a more favorable prognosis, which may be due to the immunogenicity created by the mutations in the NPM1 protein. Consequently, AML with NPM1mut can be considered an immunogenic subtype of AML. However, the underlying mechanisms of this immunogenicity and associated favorable survival outcomes need to be further investigated. Immune checkpoint molecules, such as the programmed cell death-1 (PD-1) protein and its ligand, PD-L1, play important roles in leukemogenesis through their maintenance of an immunosuppressive tumor microenvironment. Preclinical trials have shown that the use of PD-1/PD-L1 checkpoint inhibitors in solid tumors and lymphoma work best in novel therapy combinations. Patients with AML NPM1mut may be better suited to immunogenic strategies that are based on the inhibition of the PD-1 immune checkpoint pathway than patients without this mutation, suggesting the genetic landscape of patients may also inform best practice for the use of PD-1 inhibitors.
Collapse
Affiliation(s)
- Jochen Greiner
- Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany;
- Department of Internal Medicine, Diakonie Hospital Stuttgart, 70176 Stuttgart, Germany
| | - Eithar Mohamed
- Centre for Biomedicine, Hull York Medical School, University of Hull, Hull HU6 7RX, UK; (E.M.); (D.M.F.)
| | - Daniel M. Fletcher
- Centre for Biomedicine, Hull York Medical School, University of Hull, Hull HU6 7RX, UK; (E.M.); (D.M.F.)
| | - Patrick J. Schuler
- Department of Otorhinolaryngology, University Hospital Ulm, 89075 Ulm, Germany;
- Department of Oto-Rhino-Laryngology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Hubert Schrezenmeier
- Institute of Transfusion Medicine, University of Ulm, 89073 Ulm, Germany;
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, 89081 Ulm, Germany
| | - Marlies Götz
- Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany;
- Department of Internal Medicine, Diakonie Hospital Stuttgart, 70176 Stuttgart, Germany
| | - Barbara-ann Guinn
- Centre for Biomedicine, Hull York Medical School, University of Hull, Hull HU6 7RX, UK; (E.M.); (D.M.F.)
| |
Collapse
|
|
4
|
Deng DX, Ma XH, Wu ZH, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, Chen YH, Han W, Wang FR, Wang JZ, Huang XJ, Zhao XS, Mo XD. Pre-transplantation levels of lysine (K)-specific methyltransferase 2A ( KMT2A) partial tandem duplications can predict relapse of acute myeloid leukemia patients following haploidentical donor hematopoietic stem cell transplantation. BLOOD SCIENCE 2024; 6:e00207. [PMID: 39328249 PMCID: PMC11427034 DOI: 10.1097/bs9.0000000000000207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 08/29/2024] [Indexed: 09/28/2024] Open
Abstract
We aimed to identify dynamic changes of lysine (K)-specific methyltransferase 2A partial tandem duplications (KMT2A-PTD) before and after haploidentical donor hematopoietic stem cell transplantation (HID HSCT) and explore the prognostic value of pre-transplantation levels of KMT2A-PTD in acute myeloid leukemia (AML) receiving HID HSCT. Consecutive 64 AML patients with KMT2A-PTD positivity at diagnosis receiving HID HSCT were included in this study. Patients with KMT2A-PTD ≥1% before HSCT had a slower decrease of KMT2A-PTD after HID HSCT. Patients with KMT2A-PTD ≥1% before HID HSCT had a higher cumulative incidence of relapse (36.4%, 95% confidence interval [CI]: 6.3%-66.5%) at 2 years after HSCT than those with KMT2A-PTD <1% (7.5%, 95% CI: 0.3%-14.7%, P = .010). In multivariable analysis, KMT2A-PTD ≥1% before HID HSCT was the only independent risk factor for relapse (hazard ratio [HR]: 4.90; 95% CI: 1.22-19.59; P = .025). Thus, pre-transplantation levels of KMT2A-PTD could predict relapse in AML patients following HID HSCT.
Collapse
Affiliation(s)
- Dao-Xing Deng
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xiao-Hang Ma
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Ze-Hua Wu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Chen-Hua Yan
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Huan Chen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Yu-Hong Chen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Wei Han
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Feng-Rong Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Jing-Zhi Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Xiao-Su Zhao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing, China
| | - Xiao-Dong Mo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing, China
| |
Collapse
|
|
5
|
Caliskan G, Pawitan Y, Vu TN. Similarities and differences of bone marrow and peripheral blood samples from acute myeloid leukemia patients in terms of cellular heterogeneity and ex-vivo drug sensitivity. EJHAEM 2024; 5:721-727. [PMID: 39157629 PMCID: PMC11327724 DOI: 10.1002/jha2.961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 05/28/2024] [Indexed: 08/20/2024]
Abstract
Background Bone marrow (BM) evaluation is the de facto standard for diagnosis, molecular analysis, risk stratification, and therapy response assessment in acute myeloid leukemia (AML), but in patients with a high number of circulating blast cells, the peripheral blood (PB) sample could provide similar information as BM. However, there is no large-scale molecular study comparing the two specimens in terms of their gene expression profiles, cellular heterogeneities, and ex-vivo drug sensitivity. Methodology We used (i) the BEAT-AML cohort each with detailed molecular data; (ii) cell-type deconvolution to estimate leukemic and immune cell proportions between specimen types; (iii) differential expression (DE) and drug-cell type association analysis; and (iv) logistic regression models to assess the association between induction therapy response, cell-type composition and first-line drug treatment. Results Results: We identified 207 patients having BM and 116 patients having PB samples. There was a total of 1271 DE genes (false discovery rate < 0.05) between BM and PB; the top enriched pathways in terms of DE genes belong to the immune system pathways. Aggregated ex-vivo drug response profiles from the two specimens were largely similar, as were the cellular components, except for the GMP-like cell type (17% in BM vs. 5% in PB, p-value = 2 × 10-7). Among the specimen-specific results, the GMP-like subtype was associated with multiple drug resistance in BM and the ProMono-like subtype in PB. Several cell types were associated with the response to induction therapy, but the impact of specimen type on the interaction of cell type and cytarabine-associated induction therapy was not statistically significant for most cell types. Results Conclusions: Even though there are molecular and cellular differences between BM and PB samples, they show many similarities in ex-vivo drug response profiles, indicating the clinical utility of the substantially less-invasive PB samples.
Collapse
Affiliation(s)
- Gulser Caliskan
- Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
| | - Yudi Pawitan
- Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
| | - Trung Nghia Vu
- Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
| |
Collapse
|
|
6
|
Seto A, Downs G, King O, Salehi-Rad S, Baptista A, Chin K, Grenier S, Nwachukwu B, Tierens A, Minden MD, Smith AC, Capo-Chichi JM. Genomic Characterization of Partial Tandem Duplication Involving the KMT2A Gene in Adult Acute Myeloid Leukemia. Cancers (Basel) 2024; 16:1693. [PMID: 38730645 PMCID: PMC11082951 DOI: 10.3390/cancers16091693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/20/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Gene rearrangements affecting KMT2A are frequent in acute myeloid leukemia (AML) and are often associated with a poor prognosis. KMT2A gene fusions are often detected by chromosome banding analysis and confirmed by fluorescence in situ hybridization. However, small intragenic insertions, termed KMT2A partial tandem duplication (KMT2A-PTD), are particularly challenging to detect using standard molecular and cytogenetic approaches. METHODS We have validated the use of a custom hybrid-capture-based next-generation sequencing (NGS) panel for comprehensive profiling of AML patients seen at our institution. This NGS panel targets the entire consensus coding DNA sequence of KMT2A. To deduce the presence of a KMT2A-PTD, we used the relative ratio of KMT2A exons coverage. We sought to corroborate the KMT2A-PTD NGS results using (1) multiplex-ligation probe amplification (MLPA) and (2) optical genome mapping (OGM). RESULTS We analyzed 932 AML cases and identified 41 individuals harboring a KMT2A-PTD. MLPA, NGS, and OGM confirmed the presence of a KMT2A-PTD in 22 of the cases analyzed where orthogonal testing was possible. The two false-positive KMT2A-PTD calls by NGS could be explained by the presence of cryptic structural variants impacting KMT2A and interfering with KMT2A-PTD analysis. OGM revealed the nature of these previously undetected gene rearrangements in KMT2A, while MLPA yielded inconclusive results. MLPA analysis for KMT2A-PTD is limited to exon 4, whereas NGS and OGM resolved KMT2A-PTD sizes and copy number levels. CONCLUSIONS KMT2A-PTDs are complex gene rearrangements that cannot be fully ascertained using a single genomic platform. MLPA, NGS panels, and OGM are complementary technologies applied in standard-of-care testing for AML patients. MLPA and NGS panels are designed for targeted copy number analysis; however, our results showed that integration of concurrent genomic alterations is needed for accurate KMT2A-PTD identification. Unbalanced chromosomal rearrangements overlapping with KMT2A can interfere with the diagnostic sensitivity and specificity of copy-number-based KMT2A-PTD detection methodologies.
Collapse
Affiliation(s)
- Andrew Seto
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
| | - Gregory Downs
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
| | - Olivia King
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
| | - Shabnam Salehi-Rad
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
| | - Ana Baptista
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
| | - Kayu Chin
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
| | - Sylvie Grenier
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
| | - Bevoline Nwachukwu
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
| | - Anne Tierens
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada;
- Division of Hematology and Transfusion Medicine, Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada
| | - Mark D. Minden
- Department of Medicine Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2M9, Canada;
| | - Adam C. Smith
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada;
| | - José-Mario Capo-Chichi
- Genome Diagnostics & Cancer Cytogenetics Laboratories, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada; (A.S.); (G.D.); (O.K.); (S.S.-R.); (A.B.); (K.C.); (S.G.); (B.N.)
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada;
| |
Collapse
|
|
7
|
Kurzer JH, Weinberg OK. Updates in molecular genetics of acute myeloid leukemia. Semin Diagn Pathol 2023; 40:140-151. [PMID: 37059636 DOI: 10.1053/j.semdp.2023.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 04/04/2023] [Indexed: 04/16/2023]
Abstract
Acute myeloid leukemia (AML) is a type of cancer caused by aggressive neoplastic proliferations of immature myeloid cells that is fatal if untreated. AML accounts for 1.0% of all new cancer cases in the United States, with a 5-year relative survival rate of 30.5%. Once defined primarily morphologically, advances in next generational sequencing have expanded the role of molecular genetics in categorizing the disease. As such, both the World Health Organization Classification of Haematopoietic Neoplasms and The International Consensus Classification System now define a variety of AML subsets based on mutations in driver genes such as NPM1, CEBPA, TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2. This article provides an overview of some of the genetic mutations associated with AML and compares how the new classification systems incorporate molecular genetics into the definition of AML.
Collapse
Affiliation(s)
- Jason H Kurzer
- Department of Pathology, Stanford University Medical School, Palo Alto, CA, United States.
| | - Olga K Weinberg
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, United States
| |
Collapse
|
|
8
|
Soler G, Ouedraogo ZG, Goumy C, Lebecque B, Aspas Requena G, Ravinet A, Kanold J, Véronèse L, Tchirkov A. Optical Genome Mapping in Routine Cytogenetic Diagnosis of Acute Leukemia. Cancers (Basel) 2023; 15:cancers15072131. [PMID: 37046792 PMCID: PMC10093111 DOI: 10.3390/cancers15072131] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/31/2023] [Accepted: 04/01/2023] [Indexed: 04/14/2023] Open
Abstract
Cytogenetic aberrations are found in 65% of adults and 75% of children with acute leukemia. Specific aberrations are used as markers for the prognostic stratification of patients. The current standard cytogenetic procedure for acute leukemias is karyotyping in combination with FISH and RT-PCR. Optical genome mapping (OGM) is a new technology providing a precise identification of chromosomal abnormalities in a single approach. In our prospective study, the results obtained using OGM and standard techniques were compared in 29 cases of acute myeloid (AML) or lymphoblastic leukemia (ALL). OGM detected 73% (53/73) of abnormalities identified by standard methods. In AML cases, two single clones and three subclones were missed by OGM, but the assignment of patients to cytogenetic risk groups was concordant in all patients. OGM identified additional abnormalities in six cases, including one cryptic structural variant of clinical interest and two subclones. In B-ALL cases, OGM correctly detected all relevant aberrations and revealed additional potentially targetable alterations. In T-ALL cases, OGM characterized a complex karyotype in one case and identified additional abnormalities in two others. In conclusion, OGM is an attractive alternative to current multiple cytogenetic testing in acute leukemia that simplifies the procedure and reduces costs.
Collapse
Affiliation(s)
- Gwendoline Soler
- Cytogénétique Médicale, CHU Clermont-Ferrand, CHU Estaing, 63000 Clermont-Ferrand, France
| | - Zangbéwendé Guy Ouedraogo
- Cytogénétique Médicale, CHU Clermont-Ferrand, CHU Estaing, 63000 Clermont-Ferrand, France
- Service de Biochimie et Génétique Moléculaire, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France
- CNRS, INSERM, iGReD, Université Clermont Auvergne, 63001 Clermont-Ferrand, France
| | - Carole Goumy
- Cytogénétique Médicale, CHU Clermont-Ferrand, CHU Estaing, 63000 Clermont-Ferrand, France
- INSERM U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
| | | | - Gaspar Aspas Requena
- Hématologie Clinique Adulte et de Thérapie Cellulaire, CHU Estaing, 63100 Clermont-Ferrand, France
| | - Aurélie Ravinet
- Hématologie Clinique Adulte et de Thérapie Cellulaire, CHU Estaing, 63100 Clermont-Ferrand, France
| | - Justyna Kanold
- Service d'Hématologie et d'Oncologie Pédiatrique et Unité CRECHE (Centre de REcherche Clinique CHez l'Enfant), CHU Estaing, 63100 Clermont-Ferrand, France
| | - Lauren Véronèse
- Cytogénétique Médicale, CHU Clermont-Ferrand, CHU Estaing, 63000 Clermont-Ferrand, France
- Clonal Heterogeneity and Leukemic Environment in Therapy Resistance of Chronic Leukemias (CHELTER), EA7453, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
| | - Andrei Tchirkov
- Cytogénétique Médicale, CHU Clermont-Ferrand, CHU Estaing, 63000 Clermont-Ferrand, France
- Clonal Heterogeneity and Leukemic Environment in Therapy Resistance of Chronic Leukemias (CHELTER), EA7453, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
| |
Collapse
|
|
9
|
Liu XX, Pan XA, Gao MG, Kong J, Jiang H, Chang YJ, Zhang XH, Wang Y, Liu KY, Chen Z, Zhao XS, Huang XJ. The adverse impact of ecotropic viral integration site-1 (EVI1) overexpression on the prognosis of acute myeloid leukemia with KMT2A gene rearrangement in different risk stratification subtypes. Int J Lab Hematol 2023; 45:195-203. [PMID: 36358022 DOI: 10.1111/ijlh.13987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 10/17/2022] [Indexed: 11/13/2022]
Abstract
INTRODUCTION AML patients with KMT2A-MLLT3 and other 11q23 abnormalities belong to the intermediate and high-risk level groups, respectively. Whether the poor prognostic value of Ecotropic Viral Integration site-1 (EVI1) overexpression suits either the subtypes of KMT2A-MLLT3 or Non-KMT2A-MLLT3 AML patients (intermediate and high risk group) needs to be further investigated. METHODS We retrospectively analyzed the clinical characteristics of 166 KMT2A-r and KMT2A-PTD AML patients. RESULTS For the Non-KMT2A-MLLT3 group, patients in the EVI1-high subgroup had shorter OS and DFS and higher CIR than those in the EVI1-low subgroup (p = .027, p = .018, and p = .020, respectively). Additionally, both KMT2A-MLLT3 and Non-KMT2A-MLLT3 patients who received chemotherapy alone had poorer prognosis than patients who also received allogeneic hematopoietic stem cell transplant (allo-HSCT) regardless of their EVI1 expression level (all p < .001). For transplanted patients with KMT2A-MLLT3 or Non-KMT2A-MLLT3 rearrangement, the EVI1-high subgroup had worse prognosis than the EVI1-low subgroup (all p < .05). The 2-year CIR of the KMT2A-MLLT3 and Non-KMT2A-MLLT3 groups with high EVI1 expression was high (52% and 49.6%, respectively). However, for patients with low EVI1 expression, the 2-year CIR of transplanted patients with KMT2A-MLLT3 and Non-KMT2A-MLLT3 was relatively low. CONCLUSIONS Our study showed that for the Non-KMT2A-MLLT3 group, the EVI1-high group had shorter OS and DFS than the EVI1-low group. High EVI1 expression showed an adverse effect in AML with KMT2A rearrangement in different risk stratification subtypes. For the EVI1-high patients with non-KMT2A-MLLT3 rearrangement, other novel regimens towards relapse should be taken into consideration.
Collapse
Affiliation(s)
- Xin-Xin Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Beijing Hightrust Diagnostics, Co., Ltd, Beijing, China
| | - Xin-An Pan
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Meng-Ge Gao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Jun Kong
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Hao Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Ying-Jun Chang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Kai-Yan Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Zhong Chen
- Beijing Hightrust Diagnostics, Co., Ltd, Beijing, China
| | - Xiao-Su Zhao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Beijing Hightrust Diagnostics, Co., Ltd, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
| |
Collapse
|
|
10
|
Zha J, Zhong M, Pan G, Chen Q, Jiang Y, Lai Q, Tan J, Zhou H, Wu H, Xu B. Stratification and therapeutic potential of ELL in cytogenetic normal acute myeloid leukemia. Gene 2023; 856:147110. [PMID: 36543308 DOI: 10.1016/j.gene.2022.147110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 11/25/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022]
Abstract
Optimizing prognostic stratification of patients with cytogenetic normal acute myeloid leukemia (CN-AML), a highly heterogeneous subgroup in AML, appears to be important to improve its treatment and clinical outcome. Here, we report a potential role of ELL, a gene associated with leukemogenesis in AML, in prognostic stratification of CN-AML patients. By analyzing public available databases, we found that ELL was highly expressed in AML patients compared with healthy donors. Kaplan-Meier analysis revealed that ELL expression markedly correlated with short overall survival (OS) of CN-AML patients. In COX multivariable regression analysis, higher ELL expression was an independent prognostic factor for OS in CN-AML. Knockdown of ELL by shRNAs sensitized KG-1α cells to anti-leukemic agents such as idarubicin (IDA) and chidamide (CS055), supporting its role in therapeutic response and outcome in AML. To understand its function in CN-AML, we further analyzed the ELL-driving gene signature. ELL-related genes were particularly enriched in cell adhesion molecules, cell differentiation, pathways in cancer, sequence-specific DNA binding, and extracellular matrix (ECM)-receptor interaction. Analysis of the PPI network identified 25 hub genes, including the stem cell gene BMP4. While BMP4 expression was significantly associated with ELL in CN-AML, knockdown of ELL markedly down-regulated BMP4 expression, suggesting that ELL might function via regulating BMP4 in AML. Together, these observations suggest a novel mechanism underlying pro-leukemogenic role of ELL via BMP4 up-regulation in AML and its potential value to serve as a predictive biomarker for therapeutic response and outcome of CN-AML patients.
Collapse
Affiliation(s)
- Jie Zha
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China
| | - Mengya Zhong
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China
| | - Guangchao Pan
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China
| | - Qinwei Chen
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China
| | - Yuelong Jiang
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China
| | - Qian Lai
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China
| | - Jinshui Tan
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China
| | - Hui Zhou
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China
| | - Hua Wu
- Department of Nuclear Medicine, the First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China.
| | - Bing Xu
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen 361003, China.
| |
Collapse
|
|
11
|
Ye W, Ma M, Wu X, Deng J, Liu X, Zheng X, Gong Y. Prognostic significance of KMT2A-PTD in patients with acute myeloid leukaemia: a systematic review and meta-analysis. BMJ Open 2023; 13:e062376. [PMID: 36725100 PMCID: PMC9896228 DOI: 10.1136/bmjopen-2022-062376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVES Whether KMT2A-PTD has a prognostic impact on patients with acute myeloid leukaemia (AML) is controversial. Therefore, we conducted a meta-analysis to assess the prognostic value of KMT2A-PTD in patients with AML. METHODS Eligibility criteria: we included studies concerning the prognostic value of KMT2A-PTD in patients with AML. INFORMATION SOURCES Eligible studies were identified from PubMed, Embase, Medline, Web of Science, Cochrane Library and Chinese Biomedical Database. The systematic search date was 19 December 2020.Risk of bias: Sensitivity analysis was used to evaluate the stability and reliability of the combined results. Begg's and Egger's tests were used to assess the publication biases of studies. SYNTHESIS OF RESULTS We calculated the pooled HRs and their 95% CIs for overall survival (OS) and event-free survival (EFS) by Stata V.12 software. RESULTS Included studies: 18 studies covering 6499 patients were included. SYNTHESIS OF RESULTS KMT2A-PTD conferred shorter OS in total population (HR=1.30, 95% CI 1.09 to 1.51). In the subgroup analysis, KMT2A-PTD also resulted in shorter OS in karyotypically normal AML patients (HR=2.72, 95% CI 1.83 to 3.61) and old AML patients (HR=1.93, 95% CI 1.44 to 2.42). KMT2A-PTD indicated no prognostic impact on EFS in total population (HR=1.26, 95% CI 0.86 to 1.66). However, in the sensitivity analysis, KMT2A-PTD resulted in poor EFS (HR=1.34, 95% CI 1.04 to 1.64) when deleting the study with a relatively obvious effect on the combined HR. In the subgroup analysis, KMT2A-PTD was associated with poor EFS in old AML patients (HR=1.64, 95% CI 1.25 to 2.03). CONCLUSION The findings indicated that KMT2A-PTD had an adverse impact on the prognosis of patients with AML in the total population, and the conclusion can also be applied to some subgroups including karyotypically normal AML and old AML patients. KMT2A-PTD may be a promising genetic biomarker in patients with AML in the future. TRIAL REGISTRATION NUMBER CRD42021227185.
Collapse
Affiliation(s)
- Wu Ye
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Mingzhu Ma
- Department of Outpatient, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Xia Wu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jili Deng
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoyan Liu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xue Zheng
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuping Gong
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
|
12
|
Gerding WM, Tembrink M, Nilius‐Eliliwi V, Mika T, Dimopoulos F, Ladigan‐Badura S, Eckhardt M, Pohl M, Wünnenberg M, Farshi P, Reimer P, Schroers R, Nguyen HP, Vangala DB. Optical genome mapping reveals additional prognostic information compared to conventional cytogenetics in
AML
/
MDS
patients. Int J Cancer 2022; 150:1998-2011. [DOI: 10.1002/ijc.33942] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/27/2021] [Accepted: 01/13/2022] [Indexed: 11/12/2022]
Affiliation(s)
- Wanda M. Gerding
- Department for Human Genetics Ruhr‐University Bochum Bochum Germany
| | - Marco Tembrink
- Department for Human Genetics Ruhr‐University Bochum Bochum Germany
| | - Verena Nilius‐Eliliwi
- Department for Human Genetics Ruhr‐University Bochum Bochum Germany
- Department of Medicine, Hematology and Oncology Knappschaftskrankenhaus, Ruhr‐University Bochum Bochum Germany
| | - Thomas Mika
- Department of Medicine, Hematology and Oncology Knappschaftskrankenhaus, Ruhr‐University Bochum Bochum Germany
| | - Fotios Dimopoulos
- Department of Medicine, Hematology and Oncology Knappschaftskrankenhaus, Ruhr‐University Bochum Bochum Germany
| | - Swetlana Ladigan‐Badura
- Department of Medicine, Hematology and Oncology Knappschaftskrankenhaus, Ruhr‐University Bochum Bochum Germany
| | - Matthias Eckhardt
- Department of Medicine, Hematology and Oncology Knappschaftskrankenhaus, Ruhr‐University Bochum Bochum Germany
| | - Michael Pohl
- Department of Medicine, Hematology and Oncology Knappschaftskrankenhaus, Ruhr‐University Bochum Bochum Germany
| | - Max Wünnenberg
- Department of Medicine, Hematology and Oncology Knappschaftskrankenhaus, Ruhr‐University Bochum Bochum Germany
| | - Pakhshan Farshi
- Department of Hematology and Oncology Kliniken Essen‐Mitte Essen Germany
| | - Peter Reimer
- Department of Hematology and Oncology Kliniken Essen‐Mitte Essen Germany
| | - Roland Schroers
- Department of Medicine, Hematology and Oncology Knappschaftskrankenhaus, Ruhr‐University Bochum Bochum Germany
| | - Huu Phuc Nguyen
- Department for Human Genetics Ruhr‐University Bochum Bochum Germany
| | - Deepak B. Vangala
- Department of Medicine, Hematology and Oncology Knappschaftskrankenhaus, Ruhr‐University Bochum Bochum Germany
| |
Collapse
|
|
13
|
Issa GC, Zarka J, Sasaki K, Qiao W, Pak D, Ning J, Short NJ, Haddad F, Tang Z, Patel KP, Cuglievan B, Daver N, DiNardo CD, Jabbour E, Kadia T, Borthakur G, Garcia-Manero G, Konopleva M, Andreeff M, Kantarjian HM, Ravandi F. Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements. Blood Cancer J 2021; 11:162. [PMID: 34588432 PMCID: PMC8481264 DOI: 10.1038/s41408-021-00557-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/03/2021] [Accepted: 09/08/2021] [Indexed: 12/15/2022] Open
Abstract
Acute myeloid leukemia (AML) with rearrangement of the lysine methyltransferase 2a gene (KMT2Ar) has adverse outcomes. However, reports on the prognostic impact of various translocations causing KMT2Ar are conflicting. Less is known about associated mutations and their prognostic impact. In a retrospective analysis, we identified 172 adult patients with KMT2Ar AML and compared them to 522 age-matched patients with diploid AML. KMT2Ar AML had fewer mutations, most commonly affecting RAS and FLT3 without significant impact on prognosis, except for patients with ≥2 mutations with lower overall survival (OS). KMT2Ar AML had worse outcomes compared with diploid AML when newly diagnosed and at relapse, especially following second salvage (median OS of 2.4 vs 4.8 months, P < 0.0001). Therapy-related KMT2Ar AML (t-AML) had worse outcomes compared with de novo KMT2Ar AML (median OS of 0.7 years vs 1.4 years, P < 0.0001). Allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission was associated with improved OS (5-year, 52 vs 14% for no allo-HSCT, P < 0.0001). In a multivariate analysis, translocation subtypes causing KMT2Ar did not predict survival, unlike age and allo-HSCT. In conclusion, KMT2Ar was associated with adverse outcomes regardless of translocation subtype. Therefore, AML risk stratification guidelines should include all KMT2Ar as adverse.
Collapse
MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Female
- Gene Rearrangement
- Hematopoietic Stem Cell Transplantation
- Histone-Lysine N-Methyltransferase/genetics
- Humans
- Leukemia, Myeloid, Acute/diagnosis
- Leukemia, Myeloid, Acute/epidemiology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/therapy
- Male
- Middle Aged
- Mutation
- Myeloid-Lymphoid Leukemia Protein/genetics
- Prognosis
- Retrospective Studies
- Survival Analysis
- Transplantation, Homologous
- Young Adult
Collapse
Affiliation(s)
- Ghayas C Issa
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA.
| | - Jabra Zarka
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, PA, Pittsburgh, USA
| | - Koji Sasaki
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Wei Qiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Daewoo Pak
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
- Division of Data Science, Yonsei University, Wonju, South Korea
| | - Jing Ning
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Nicholas J Short
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Fadi Haddad
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Zhenya Tang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Keyur P Patel
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Branko Cuglievan
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Naval Daver
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Courtney D DiNardo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Elias Jabbour
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Tapan Kadia
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Gautam Borthakur
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | | | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Michael Andreeff
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Hagop M Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA
| | - Farhad Ravandi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, TX, Houston, USA.
| |
Collapse
|
|
14
|
Therapeutic implications of menin inhibition in acute leukemias. Leukemia 2021; 35:2482-2495. [PMID: 34131281 DOI: 10.1038/s41375-021-01309-y] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/19/2021] [Accepted: 05/24/2021] [Indexed: 01/31/2023]
Abstract
Menin inhibitors are novel targeted agents currently in clinical development for the treatment of genetically defined subsets of acute leukemia. Menin has a tumor suppressor function in endocrine glands. Germline mutations in the gene encoding menin cause the multiple endocrine neoplasia type 1 (MEN1) syndrome, a hereditary condition associated with tumors of the endocrine glands. However, menin is also critical for leukemogenesis in subsets driven by rearrangement of the Lysine Methyltransferase 2A (KMT2A) gene, previously known as mixed-lineage leukemia (MLL), which encodes an epigenetic modifier. These seemingly opposing functions of menin can be explained by its various roles in gene regulation. Therefore, leukemias with rearrangement of KMT2A are predicted to respond to menin inhibition with early clinical data validating this proof-of-concept. These leukemias affect infants, children and adults, and lead to adverse outcomes with current standard therapies. Recent studies have identified novel targets in acute leukemia that are susceptible to menin inhibition, such as mutated Nucleophosmin 1 (NPM1), the most common genetic alteration in adult acute myeloid leukemia (AML). In addition to these alterations, other leukemia subsets with similar transcriptional dependency could be targeted through menin inhibition. This led to rationally designed clinical studies, investigating small-molecule oral menin inhibitors in relapsed acute leukemias with promising early results. Herein, we discuss the physiologic and malignant biology of menin, the mechanisms of leukemia in these susceptible subsets, and future therapeutic strategies using these inhibitors in acute leukemia.
Collapse
|
|
15
|
Dai B, Yu H, Ma T, Lei Y, Wang J, Zhang Y, Lu J, Yan H, Jiang L, Chen B. The Application of Targeted RNA Sequencing for KMT2A-Partial Tandem Duplication Identification and Integrated Analysis of Molecular Characterization in Acute Myeloid Leukemia. J Mol Diagn 2021; 23:1478-1490. [PMID: 34384895 DOI: 10.1016/j.jmoldx.2021.07.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/12/2021] [Accepted: 07/26/2021] [Indexed: 12/25/2022] Open
Abstract
The partial tandem duplication of histone-lysine N-methyltransferase 2A (KMT2A-PTD) is an important genetic alteration in acute myeloid leukemia (AML) and is associated with poor clinical outcome. Accurate and rapid detection of KMT2A-PTD is important for outcome prediction and clinical management, but next-generation sequencing-based quantitative research is still lacking. In this study, we developed a targeted RNA-based next-generation sequencing panel, together with single primer enrichment and unique molecular identifiers, to identify KMT2A-PTD as well as AML-related gene fusions and other driver mutations. Our panel showed high sensitivity, accuracy, and reproducibility in detecting the fusion ratio of KMT2A-PTD. We characterized the mutation profile of KMT2A-PTD-positive patients with AML and found different distribution patterns of driver mutations according to KMT2A-PTD fusion ratio level. Survival analyses revealed that the fusion ratio of KMT2A-PTD did not affect clinical outcome, but a novel molecular combination, namely, KMT2A-PTD/DNMT3A/FMS-like tyrosine kinase 3-internal tandem duplication, was associated with poor prognosis. Finally, we proved that the dynamic changes in the KMT2A-PTD fusion ratio were consistent with the overall process of disease progression. In summary, we applied the unique molecular identifier-based RNA panel to quantitatively detect KMT2A-PTD and elucidate its clinical relevance, which complemented the integrative network of various genetic alterations in AML.
Collapse
Affiliation(s)
- Bing Dai
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Yu
- Jiangsu Key Laboratory of Zoonosis and Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonose, Yangzhou University, Yangzhou, China
| | - Tingting Ma
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yichen Lei
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiyue Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yunxiang Zhang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Lu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Han Yan
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Jiang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Bing Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
16
|
Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML. Blood Adv 2021; 5:1003-1016. [PMID: 33591326 DOI: 10.1182/bloodadvances.2020002517] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 12/10/2020] [Indexed: 12/19/2022] Open
Abstract
Although copy number alterations (CNAs) and translocations constitute the backbone of the diagnosis and prognostication of acute myeloid leukemia (AML), techniques used for their assessment in routine diagnostics have not been reconsidered for decades. We used a combination of 2 next-generation sequencing-based techniques to challenge the currently recommended conventional cytogenetic analysis (CCA), comparing the approaches in a series of 281 intensively treated patients with AML. Shallow whole-genome sequencing (sWGS) outperformed CCA in detecting European Leukemia Net (ELN)-defining CNAs and showed that CCA overestimated monosomies and suboptimally reported karyotype complexity. Still, the concordance between CCA and sWGS for all ELN CNA-related criteria was 94%. Moreover, using in silico dilution, we showed that 1 million reads per patient would be enough to accurately assess ELN-defining CNAs. Total genomic loss, defined as a total loss ≥200 Mb by sWGS, was found to be a better marker for genetic complexity and poor prognosis compared with the CCA-based definition of complex karyotype. For fusion detection, the concordance between CCA and whole-transcriptome sequencing (WTS) was 99%. WTS had better sensitivity in identifying inv(16) and KMT2A rearrangements while showing limitations in detecting lowly expressed PML-RARA fusions. Ligation-dependent reverse transcription polymerase chain reaction was used for validation and was shown to be a fast and reliable method for fusion detection. We conclude that a next-generation sequencing-based approach can replace conventional CCA for karyotyping, provided that efforts are made to cover lowly expressed fusion transcripts.
Collapse
|
|
17
|
Antherieu G, Bidet A, Huet S, Hayette S, Migeon M, Boureau L, Sujobert P, Thomas X, Ghesquières H, Pigneux A, Heiblig M. Allogenic Stem Cell Transplantation Abrogates Negative Impact on Outcome of AML Patients with KMT2A Partial Tandem Duplication. Cancers (Basel) 2021; 13:cancers13092272. [PMID: 34068470 PMCID: PMC8126020 DOI: 10.3390/cancers13092272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 05/02/2021] [Accepted: 05/06/2021] [Indexed: 01/22/2023] Open
Abstract
Recently, a new subset of acute myeloid leukemia (AML) presenting a direct partial tandem duplication (PTD) of the KMT2A gene was described. The consequences of this alteration in terms of outcome and response to treatment remain unclear. We analyzed retrospectively a cohort of KMT2A-PTD-mutated patients with newly diagnosed AML. With a median follow-up of 3.6 years, the median overall survival was 12.1 months. KMT2A-PTD-mutated patients were highly enriched in mutations affecting epigenetic actors and the RTK/RAS signaling pathway. Integrating KMT2A-PTD in ELN classification abrogates its predictive value on survival suggesting that this mutation may overcome other genomic marker effects. In patients receiving intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) significantly improved the outcome compared to non-transplanted patients. In the multivariate analysis, only HSCT at any time in complete remission (HR = 2.35; p = 0.034) and FLT3-ITD status (HR = 0.29; p = 0.014) were independent variables associated with overall survival, whereas age was not. In conclusion, our results emphasize that KMT2A-PTD should be considered as a potential adverse prognostic factor. However, as KMT2A-PTD-mutated patients are usually considered an intermediate risk group, upfront HSCT should be considered in first CR due to the high relapse rate observed in this subset of patients.
Collapse
Affiliation(s)
- Gabriel Antherieu
- Department of Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France; (G.A.); (X.T.); (H.G.)
| | - Audrey Bidet
- Hematology Biology, Molecular Hematology, Bordeaux University Hospital, 33600 Pessac, France; (A.B.); (M.M.); (L.B.)
| | - Sarah Huet
- Department of Molecular Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France; (S.H.); (S.H.); (P.S.)
| | - Sandrine Hayette
- Department of Molecular Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France; (S.H.); (S.H.); (P.S.)
| | - Marina Migeon
- Hematology Biology, Molecular Hematology, Bordeaux University Hospital, 33600 Pessac, France; (A.B.); (M.M.); (L.B.)
| | - Lisa Boureau
- Hematology Biology, Molecular Hematology, Bordeaux University Hospital, 33600 Pessac, France; (A.B.); (M.M.); (L.B.)
| | - Pierre Sujobert
- Department of Molecular Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France; (S.H.); (S.H.); (P.S.)
| | - Xavier Thomas
- Department of Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France; (G.A.); (X.T.); (H.G.)
| | - Hervé Ghesquières
- Department of Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France; (G.A.); (X.T.); (H.G.)
| | - Arnaud Pigneux
- Hematology and Cell Therapy, Bordeaux University Hospital, 33600 Pessac, France;
| | - Mael Heiblig
- Department of Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre Bénite, France; (G.A.); (X.T.); (H.G.)
- Correspondence: ; Tel.: +33-478-862-240; Fax: +33-472-678-880
| |
Collapse
|
|
18
|
Grieselhuber NR, Mims AS. Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches. Curr Hematol Malig Rep 2021; 16:192-206. [PMID: 33738705 DOI: 10.1007/s11899-021-00621-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2021] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow that has a poor prognosis with traditional cytotoxic chemotherapy, especially in elderly patients. In recent years, small molecule inhibitors targeting AML-associated IDH1, IDH2, and FLT3 mutations have been FDA approved. However, the majority of AML cases do not have a targetable mutation. A variety of novel agents targeting both previously untargetable mutations and general pathways in AML are currently being investigated. Herein, we review selected new targeted therapies currently in early-phase clinical investigation in AML. RECENT FINDINGS The DOT1L inhibitor pinometostat in KMT2A-rearranged AML, the menin inhibitors KO-539 and SYNDX-5613 in KMT2Ar and NPM1-mutated AML, and the mutant TP53 inhibitor APR-246 are examples of novel agents targeting specific mutations in AML. In addition, BET inhibitors, polo-like kinase inhibitors, and MDM2 inhibitors are promising new drug classes for AML which do not depend on the presence of a particular mutation. AML remains in incurable disease for many patients but advances in genomics, epigenetics, and drug discovery have led to the development of many potential novel therapeutic agents, many of which are being investigated in ongoing clinical trials. Additional studies will be necessary to determine how best to incorporate these novel agents into routine clinical treatment of AML.
Collapse
Affiliation(s)
- Nicole R Grieselhuber
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Alice S Mims
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
| |
Collapse
|
|
19
|
Ochi Y, Ogawa S. Chromatin-Spliceosome Mutations in Acute Myeloid Leukemia. Cancers (Basel) 2021; 13:cancers13061232. [PMID: 33799787 PMCID: PMC7999050 DOI: 10.3390/cancers13061232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary Recent genomic studies have identified chromatin-spliceosome (CS)-acute myeloid leukemia (AML) as a new subgroup of AML. CS-AML is defined by several mutations that perturb epigenetic regulation, such as those affecting splicing factors, cohesin components, transcription factors, and chromatin modifiers, which are also frequently mutated in other myeloid malignancies, such as myelodysplastic syndrome and secondary AML. Thus, these mutations identify myeloid neoplasms that lie on the boundaries of conventional differential diagnosis. CS-AML shares several clinical characteristics with secondary AML. Therefore, the presence of CS-mutations may help to better classify and manage patients with AML and related disorders. The aim of this review is to discuss the genetic and clinical characteristics of CS-AML and roles of driver mutations defining this unique genomic subgroup of AML. Abstract Recent genetic studies on large patient cohorts with acute myeloid leukemia (AML) have cataloged a comprehensive list of driver mutations, resulting in the classification of AML into distinct genomic subgroups. Among these subgroups, chromatin-spliceosome (CS)-AML is characterized by mutations in the spliceosome, cohesin complex, transcription factors, and chromatin modifiers. Class-defining mutations of CS-AML are also frequently identified in myelodysplastic syndrome (MDS) and secondary AML, indicating the molecular similarity among these diseases. CS-AML is associated with myelodysplasia-related changes in hematopoietic cells and poor prognosis, and, thus, can be treated using novel therapeutic strategies and allogeneic stem cell transplantation. Functional studies of CS-mutations in mice have revealed that CS-mutations typically cause MDS-like phenotypes by altering the epigenetic regulation of target genes. Moreover, multiple CS-mutations often synergistically induce more severe phenotypes, such as the development of lethal MDS/AML, suggesting that the accumulation of many CS-mutations plays a crucial role in the progression of MDS/AML. Indeed, the presence of multiple CS-mutations is a stronger indicator of CS-AML than a single mutation. This review summarizes the current understanding of the genetic and clinical features of CS-AML and the functional roles of driver mutations characterizing this unique category of AML.
Collapse
Affiliation(s)
- Yotaro Ochi
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
- Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan
- Department of Medicine, Centre for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm 171 77, Sweden
- Correspondence: ; Tel.: +81-75-753-9285
| |
Collapse
|
|
20
|
Kirtonia A, Pandya G, Sethi G, Pandey AK, Das BC, Garg M. A comprehensive review of genetic alterations and molecular targeted therapies for the implementation of personalized medicine in acute myeloid leukemia. J Mol Med (Berl) 2020; 98:1069-1091. [PMID: 32620999 DOI: 10.1007/s00109-020-01944-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 05/18/2020] [Accepted: 06/22/2020] [Indexed: 12/17/2022]
Abstract
Acute myeloid leukemia (AML) is an extremely heterogeneous disease defined by the clonal growth of myeloblasts/promyelocytes not only in the bone marrow but also in peripheral blood and/or tissues. Gene mutations and chromosomal abnormalities are usually associated with aberrant proliferation and/or block in the normal differentiation of hematopoietic cells. So far, the combination of cytogenetic profiling and molecular and gene mutation analyses remains an essential tool for the classification, diagnosis, prognosis, and treatment for AML. This review gives an overview on how the development of novel innovative technologies has allowed us not only to detect the genetic alterations as early as possible but also to understand the molecular pathogenesis of AML to develop novel targeted therapies. We also discuss the remarkable advances made during the last decade to understand the AML genome both at primary and relapse diseases and how genetic alterations might influence the distinct biological groups as well as the clonal evolution of disease during the diagnosis and relapse. Also, the review focuses on how the persistence of epigenetic gene mutations during morphological remission is associated with relapse. It is suggested that along with the prognostic and therapeutic mutations, the novel molecular targeted therapies either approved by FDA or those under clinical trials including CART-cell therapy would be of immense importance in the effective management of AML.
Collapse
Affiliation(s)
- Anuradha Kirtonia
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, 201313, India
| | - Gouri Pandya
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, 201313, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Amit Kumar Pandey
- Amity Institute of Biotechnology (AIB), Amity University, Gurgaon, Haryana, 122413, India
| | - Bhudev C Das
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, 201313, India
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, 201313, India.
| |
Collapse
|
|
21
|
Arindrarto W, Borràs DM, de Groen RAL, van den Berg RR, Locher IJ, van Diessen SAME, van der Holst R, van der Meijden ED, Honders MW, de Leeuw RH, Verlaat W, Jedema I, Kroes WGM, Knijnenburg J, van Wezel T, Vermaat JSP, Valk PJM, Janssen B, de Knijff P, van Bergen CAM, van den Akker EB, Hoen PAC', Kiełbasa SM, Laros JFJ, Griffioen M, Veelken H. Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing. Leukemia 2020; 35:47-61. [PMID: 32127641 PMCID: PMC7787979 DOI: 10.1038/s41375-020-0762-8] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 01/17/2020] [Accepted: 02/12/2020] [Indexed: 01/12/2023]
Abstract
Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, and flexible platform for AML diagnostics. We developed HAMLET (Human AML Expedited Transcriptomics) as bioinformatics pipeline for simultaneous detection of fusion genes, small variants, tandem duplications, and gene expression with all information assembled in an annotated, user-friendly output file. Whole transcriptome RNA sequencing was performed on 100 AML cases and HAMLET results were validated by reference assays and targeted resequencing. The data showed that HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and tandem duplications in FLT3 and KMT2A were detected by a novel algorithm based on soft-clipped reads with 100% sensitivity and 97.1% specificity. In conclusion, HAMLET has the potential to provide accurate comprehensive diagnostic information relevant for AML classification, risk assessment and targeted therapy on a single technology platform.
Collapse
Affiliation(s)
- Wibowo Arindrarto
- Center for Computational Biology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands.,Department of Human Genetics, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Daniel M Borràs
- GenomeScan B.V, 2333 BZ, Leiden, The Netherlands.,Department of Chemical Cell Biology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Ruben A L de Groen
- Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Redmar R van den Berg
- Department of Human Genetics, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Irene J Locher
- Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | | | - Rosalie van der Holst
- Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | | | - M Willy Honders
- Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Rick H de Leeuw
- Forensic Laboratory for DNA Research, Department of Human Genetics, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Wina Verlaat
- Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Inge Jedema
- Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Wilma G M Kroes
- Department of Clinical Genetics, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Jeroen Knijnenburg
- Department of Clinical Genetics, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Tom van Wezel
- Department of Pathology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Joost S P Vermaat
- Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Peter J M Valk
- Department of Hematology, Erasmus University Medical Center, 3015CN, Rotterdam, The Netherlands
| | - Bart Janssen
- GenomeScan B.V, 2333 BZ, Leiden, The Netherlands
| | - Peter de Knijff
- Forensic Laboratory for DNA Research, Department of Human Genetics, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | | | - Erik B van den Akker
- Center for Computational Biology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands.,The Delft Bioinformatics Lab, Delft University of Technology, 2628CD, Delft, The Netherlands.,Section of Molecular Epidemiology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Peter A C 't Hoen
- Department of Human Genetics, Leiden University Medical Center, 2300RC, Leiden, The Netherlands.,The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands
| | - Szymon M Kiełbasa
- Center for Computational Biology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Jeroen F J Laros
- Department of Human Genetics, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| | - Marieke Griffioen
- Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands.
| | - Hendrik Veelken
- Department of Hematology, Leiden University Medical Center, 2300RC, Leiden, The Netherlands
| |
Collapse
|
|
22
|
Vetro C, Haferlach T, Meggendorfer M, Stengel A, Jeromin S, Kern W, Haferlach C. Cytogenetic and molecular genetic characterization of KMT2A-PTD positive acute myeloid leukemia in comparison to KMT2A-Rearranged acute myeloid leukemia. Cancer Genet 2019; 240:15-22. [PMID: 31698332 DOI: 10.1016/j.cancergen.2019.10.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 09/23/2019] [Accepted: 10/28/2019] [Indexed: 12/19/2022]
Abstract
To define the biological differences in acute myeloid leukaemia (AML) with KMT2A gene involvements and their prognostic impact, we compared 190 de novo AML patients at diagnosis, 95 harbouring KMT2A-rearrangement (KMT2Ar) and 95 KMT2A-PTD by performing cytogenetic and molecular genetic analyses. Both AML subtypes had an unfavourable outcome, particularly in patients > 60 years. Patients with KMT2Ar were younger compared to patients with KMT2A-PTD (mean 52 vs 65 years, p < 0.001) and had a higher rate of additional cytogenetic abnormalities (ACA) (46% vs 25% of cases). In both groups, occurrence of ACA did not influence the overall survival (OS). Regarding molecular genetics, 66% of patients with KMT2Ar and 99% of patients with KMT2A-PTD had additional gene mutations. In multivariate analysis, KRAS mutations and 10p12 rearrangement resulted as adverse prognostic factors in KMT2Ar subgroup. In the KMT2A-PTD group, apart from age, only the occurrence of DNMT3A non-R882 mutations correlated with shorter OS.
Collapse
|
|
23
|
Gambacorta V, Gnani D, Vago L, Di Micco R. Epigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects. Front Cell Dev Biol 2019; 7:207. [PMID: 31681756 PMCID: PMC6797914 DOI: 10.3389/fcell.2019.00207] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 09/11/2019] [Indexed: 12/19/2022] Open
Abstract
Over the past decades, our molecular understanding of acute myeloid leukemia (AML) pathogenesis dramatically increased, thanks also to the advent of next-generation sequencing (NGS) technologies. Many of these findings, however, have not yet translated into new prognostic markers or rationales for treatments. We now know that AML is a highly heterogeneous disease characterized by a very low mutational burden. Interestingly, the few mutations identified mainly reside in epigenetic regulators, which shape and define leukemic cell identity. In the light of these discoveries and given the increasing number of drugs targeting epigenetic regulators in clinical development and testing, great interest is emerging for the use of small molecules targeting leukemia epigenome. Together with their effects on leukemia cell-intrinsic properties, such as proliferation and survival, epigenetic drugs may affect the way leukemic cells communicate with the surrounding components of the tumor and immune microenvironment. Here, we review current knowledge on alterations in the AML epigenetic landscape and discuss the promises of epigenetic therapies for AML treatment. Finally, we summarize emerging molecular studies elucidating how epigenetic rewiring in cancer cells may as well exert immune-modulatory functions, boost the immune system, and potentially contribute to better patient outcomes.
Collapse
Affiliation(s)
- Valentina Gambacorta
- Unit of Senescence in Stem Cell Aging, Differentiation and Cancer, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.,Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Milano-Bicocca University, Milan, Italy
| | - Daniela Gnani
- Unit of Senescence in Stem Cell Aging, Differentiation and Cancer, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luca Vago
- Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Raffaella Di Micco
- Unit of Senescence in Stem Cell Aging, Differentiation and Cancer, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
24
|
Skayneh H, Jishi B, Hleihel R, Hamieh M, Darwiche N, Bazarbachi A, El Sabban M, El Hajj H. A Critical Review of Animal Models Used in Acute Myeloid Leukemia Pathophysiology. Genes (Basel) 2019; 10:E614. [PMID: 31412687 PMCID: PMC6722578 DOI: 10.3390/genes10080614] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 07/30/2019] [Accepted: 08/01/2019] [Indexed: 12/24/2022] Open
Abstract
Acute myeloid leukemia (AML) is one of the most frequent, complex, and heterogeneous hematological malignancies. AML prognosis largely depends on acquired cytogenetic, epigenetic, and molecular abnormalities. Despite the improvement in understanding the biology of AML, survival rates remain quite low. Animal models offer a valuable tool to recapitulate different AML subtypes, and to assess the potential role of novel and known mutations in disease progression. This review provides a comprehensive and critical overview of select available AML animal models. These include the non-mammalian Zebrafish and Drosophila models as well as the mammalian rodent systems, comprising rats and mice. The suitability of each animal model, its contribution to the advancement of knowledge in AML pathophysiology and treatment, as well as its advantages and limitations are discussed. Despite some limitations, animal models represent a powerful approach to assess toxicity, and permit the design of new therapeutic strategies.
Collapse
Affiliation(s)
- Hala Skayneh
- Department of Experimental Pathology, Microbiology and Immunology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Batoul Jishi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Rita Hleihel
- Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Maguy Hamieh
- Department of Experimental Pathology, Microbiology and Immunology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
- Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Nadine Darwiche
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Ali Bazarbachi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
- Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Marwan El Sabban
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
| | - Hiba El Hajj
- Department of Experimental Pathology, Microbiology and Immunology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
- Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
| |
Collapse
|
|
25
|
Epigenetic Abnormalities in Acute Myeloid Leukemia and Leukemia Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019. [PMID: 31338820 DOI: 10.1007/978-981-13-7342-8_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/28/2023]
Abstract
Recently advances in cancer genomics revealed the unexpected high frequencies of epigenetic abnormalities in human acute myeloid leukemia (AML). Accumulating data suggest that these leukemia-associated epigenetic factors play critical roles in both normal hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs). In turn, these abnormalities result in susceptibilities of LSC and related diseases to epigenetic inhibitors. In this chapter, we will focus on the mutations of epigenetic factors in AML, their functional roles and mechanisms in normal hematopoiesis and leukemia genesis, especially in LSC, and potential treatment opportunities specifically for AML with epigenetic dysregulations.
Collapse
|
|
26
|
Sakhdari A, Tang Z, Ok CY, Bueso-Ramos CE, Medeiros LJ, Huh YO. Homogeneously staining region (hsr) on chromosome 11 is highly specific for KMT2A amplification in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Cancer Genet 2019; 238:18-22. [PMID: 31425921 DOI: 10.1016/j.cancergen.2019.07.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 06/24/2019] [Accepted: 07/01/2019] [Indexed: 01/01/2023]
Abstract
AML and MDS are most common myeloid neoplasms that affect mainly older patients. Overexpression of certain proto-oncogenes plays an indispensable role in tumorigenesis and overexpression can be a consequence of gene rearrangement, amplification and/or mutation. Rearrangement and amplification of KMT2A located at chromosome band 11q23 is a well-characterized genetic driver in a subset of AML/MDS cases and is associated with a poor prognosis. The presence of homogeneously staining regions (hsr) also has been correlated with amplification of specific proto-oncogenes. In this study, we correlated hsr(11)(q23) with KMT2A in a large cohort of AML/MDS (n = 54) patients. We identified 37 patients with hsr(11)(q23) in the setting of AML (n = 27) and MDS (n = 10). All patients showed a complex karyotype including 12 cases with monosomy 17. KMT2A FISH analysis was available for 35 patients which showed KMT2A amplification in all patients. Among control cases with hsr involving chromosomes other than 11q [non-11q hsr, n = 17], FISH analysis for KMT2A was available in 10 cases and none of these cases showed KMT2A amplification (p = 0.0001, Fisher's exact test, two-tailed). Mutational analysis was performed in 32 patients with hsr(11)(q23). The most common mutated gene was TP53 (n = 29), followed by DNMT3A (n = 4), NF1 (n = 4), and TET2 (n = 3). Thirty (83%) patients died over a median follow-up of 7.6 months (range, 0.4-33.4). In summary, hsr(11)(q23) in AML/MDS cases is associated with a complex karyotype, monosomy 17, KMT2A amplification, and TP53 mutation.
Collapse
Affiliation(s)
- Ali Sakhdari
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, United States.
| | - Zhenya Tang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, United States
| | - Chi Young Ok
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, United States
| | - Carlos E Bueso-Ramos
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, United States
| | - L Jeffrey Medeiros
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, United States
| | - Yang O Huh
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, United States
| |
Collapse
|
|
27
|
Cocciardi S, Dolnik A, Kapp-Schwoerer S, Rücker FG, Lux S, Blätte TJ, Skambraks S, Krönke J, Heidel FH, Schnöder TM, Corbacioglu A, Gaidzik VI, Paschka P, Teleanu V, Göhring G, Thol F, Heuser M, Ganser A, Weber D, Sträng E, Kestler HA, Döhner H, Bullinger L, Döhner K. Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation. Nat Commun 2019; 10:2031. [PMID: 31048683 PMCID: PMC6497712 DOI: 10.1038/s41467-019-09745-2] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 03/28/2019] [Indexed: 12/15/2022] Open
Abstract
Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated (NPM1mut) AML, we assess mutation status of five recurrently mutated oncogenes in 129 paired NPM1mut samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1mut loss (n = 11). To better understand these NPM1mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1mut loss patients (pts) feature distinct mutational patterns that share almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways. In contrast, profiles of pts with persistent NPM1mut are reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, though NPM1mut loss cases suggest a second "de novo" or treatment-associated AML (tAML) as alternative cause of relapse.
Collapse
Affiliation(s)
- Sibylle Cocciardi
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Anna Dolnik
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Silke Kapp-Schwoerer
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Frank G Rücker
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Susanne Lux
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Tamara J Blätte
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Sabrina Skambraks
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Jan Krönke
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Florian H Heidel
- Department of Internal Medicine II, Hematology and Oncology, Friedrich-Schiller-University Medical Center, Jena, 07743, Germany.,Leibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, 07745, Germany
| | - Tina M Schnöder
- Department of Internal Medicine II, Hematology and Oncology, Friedrich-Schiller-University Medical Center, Jena, 07743, Germany.,Leibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, 07745, Germany
| | - Andrea Corbacioglu
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Verena I Gaidzik
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Peter Paschka
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Veronica Teleanu
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Gudrun Göhring
- Institute of Cell & Molecular Pathology, Hannover Medical School, Hannover, 30625, Germany
| | - Felicitas Thol
- Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, 30625, Germany
| | - Michael Heuser
- Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, 30625, Germany
| | - Arnold Ganser
- Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, 30625, Germany
| | - Daniela Weber
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Eric Sträng
- Institute of Medical Systems Biology, Ulm University, Ulm, 30625, Germany
| | - Hans A Kestler
- Institute of Medical Systems Biology, Ulm University, Ulm, 30625, Germany
| | - Hartmut Döhner
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany
| | - Lars Bullinger
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany. .,Department of Hematology, Oncology and Tumorimmunology, Charité University Medicine, Berlin, 13353, Germany.
| | - Konstanze Döhner
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany.
| |
Collapse
|
|
28
|
Kim B, Lee H, Jang J, Kim SJ, Lee ST, Cheong JW, Lyu CJ, Min YH, Choi JR. Targeted next generation sequencing can serve as an alternative to conventional tests in myeloid neoplasms. PLoS One 2019; 14:e0212228. [PMID: 30840646 PMCID: PMC6402635 DOI: 10.1371/journal.pone.0212228] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 01/29/2019] [Indexed: 12/30/2022] Open
Abstract
The 2016 World Health Organization classification introduced a number of genes with somatic mutations and a category for germline predisposition syndromes in myeloid neoplasms. We have designed a comprehensive next-generation sequencing assay to detect somatic mutations, translocations, and germline mutations in a single assay and have evaluated its clinical utility in patients with myeloid neoplasms. Extensive and specified bioinformatics analyses were undertaken to detect single nucleotide variations, FLT3 internal tandem duplication, genic copy number variations, and chromosomal copy number variations. This enabled us to maximize the clinical utility of the assay, and we concluded that, as a single assay, it can be a good supplement for many conventional tests, including Sanger sequencing, RT-PCR, and cytogenetics. Of note, we found that 8.4-11.6% of patients with acute myeloid leukemia and 12.9% of patients with myeloproliferative neoplasms had germline mutations, and most were heterozygous carriers for autosomal recessive marrow failure syndromes. These patients often did not respond to standard chemotherapy, suggesting that germline predisposition may have distinct and significant clinical implications.
Collapse
Affiliation(s)
- Borahm Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Hyeonah Lee
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea
| | - Jieun Jang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Soo-Jeong Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Seung-Tae Lee
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
- * E-mail: (STL); (JRC)
| | - June-Won Cheong
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Chuhl Joo Lyu
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
| | - Yoo Hong Min
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Rak Choi
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
- * E-mail: (STL); (JRC)
| |
Collapse
|
|
29
|
He Z, Wang B, Chen L, Huang Y, Wang H, Yang M, Xiao X, Lu Y, Chen J, Wu Y. MLL-PTD in a 13-year-old patient with blast phase myeloproliferative neoplasm: A case report. Medicine (Baltimore) 2018; 97:e13220. [PMID: 30431598 PMCID: PMC6257502 DOI: 10.1097/md.0000000000013220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
RATIONALE The risk of leukemic transformation in myeloproliferative neoplasm (MPN) has been increasing with time. Partial Tandem Duplications of the MLL gene (MLL-PTD) has been reported in de novo acute myeloid leukemia (AML), but not in MPN blast phase. The post-MPN AML developed adverse clinical outcomes, which showed no noticeable improvement over the past 15 years. Therefore, the mechanisms and therapeutic approaches of post-MPN AML need to be deeply studied. PATIENT CONCERNS In this study, we present a JAK2V617F positive MPN patient who experienced fatigue and splenomegaly, transforming into JAK2V617F negative AML. DIAGNOSES A diagnosis of acute monocytic leukemia was made in MPN blast phase. INTERVENTIONS The patient received chemotherapy and allogeneic hematopoietic stem cell transplantation (Allo-SCT). OUTCOMES The patient achieved complete remission twice, but relapsed twice. Relapse-free survival was only 3 months. She died about 24 months after her diagnosis. LESSONS MLL-PTD occurs in the progression of JAK2V617F positive MPN into JAK2V617F negative AML, which may be a novel mechanism of MPN blast phase and helpful for post-MPN AML diagnosis. Allo-SCT may be a good choice for post-MPN AML with MLL-PTD. More therapeutic strategies need to be explored for a better prognosis in these patients.
Collapse
|
|
30
|
King RL, Bagg A. Molecular Malfeasance Mediating Myeloid Malignancies: The Genetics of Acute Myeloid Leukemia. Methods Mol Biol 2018; 1633:1-17. [PMID: 28735477 DOI: 10.1007/978-1-4939-7142-8_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A remarkable number of different, but recurrent, structural cytogenetic abnormalities have been observed in AML, and the 2016 WHO AML classification system incorporates numerous distinct entities associated with translocations or inversions, as well as others associated with single gene mutations into a category entitled "AML with recurrent genetic abnormalities." The AML classification is heavily reliant on cytogenetic and molecular information based on conventional genetic techniques (including karyotype, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, single gene sequencing), but large-scale next generation sequencing is now identifying novel mutations. With targeted next generation sequencing panels now clinically available at many centers, detection of mutations, as well as alterations in epigenetic modifiers, is becoming part of the routine diagnostic evaluation of AML and will likely impact future classification schemes.
Collapse
Affiliation(s)
- Rebecca L King
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Adam Bagg
- Division of Hematopathology, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 7103 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA, USA.
| |
Collapse
|
|
31
|
Fang JF, Yuan HN, Song YF, Sun PB, Zheng XL, Wang XJ. E-26 Transformation-specific Related Gene Expression and Outcomes in Cytogenetically Normal Acute Myeloid Leukemia: A Meta-analysis. Chin Med J (Engl) 2018; 130:1481-1490. [PMID: 28584213 PMCID: PMC5463480 DOI: 10.4103/0366-6999.207474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Background: The E-26 transformation-specific related gene (ERG) is frequently expressed in cytogenetically normal acute myeloid leukemia (CN-AML). Herein, we performed a meta-analysis to investigate the relationship between the prognostic significance of ERG expression and CN-AML. Methods: A systematic review of PubMed database and other search engines were used to identify the studies between January 2005 and November 2016. A total of 667 CN-AML patients were collected from seven published studies. Of the 667 patients underwent intensive chemotherapy, 429 had low expression of ERG and 238 had high expression of ERG. Summary odds ratio (OR) and the 95% confidence interval (CI) for the ERG expression and CN-AML were calculated using fixed- or random-effects models. Heterogeneity was assessed using Chi-squared-based Q-statistic test and I2 statistics. All statistical analyses were performed using R.3.3.1 software packages (R Foundation for Statistical Computing, Vienna, Austria) and RevMan5.3 (Cochrane Collaboration, Copenhagen, Denmark). Results: Overall, patients with high ERG expression had a worse relapse (OR = 2.5127, 95% CI: 1.5177–4.1601, P = 0.0003) and lower complete remission (OR = 0. 3495, 95% CI: 0.2418–0.5051, P < 0.0001). With regard to the known molecular markers, both internal tandem duplications of the fms-related tyrosine kinase 3 gene (OR = 3.8634, 95% CI: 1.8285–8.1626, P = 0.004) and brain and acute leukemia, cytoplasmic (OR = 3.1538, 95% CI: 2.0537–4.8432, P < 0.0001) were associated with the ERG expression. In addition, the results showed a statistical significance between French-American-British (FAB) classification subtype (minimally differentiated AML and AML without maturation, OR = 4.7902, 95% CI: 2.7772–8.2624, P < 0.0001; acute monocytic leukemia, OR = 0.2324, 95% CI: 0.0899–0.6006, P = 0.0026) and ERG expression. Conclusion: High ERG expression might be used as a strong adverse prognostic factor in CN-AML.
Collapse
Affiliation(s)
- Jian-Fei Fang
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013; Institute of Lung Cancer, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013, China
| | - Hai-Ning Yuan
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013, China
| | - Yong-Fei Song
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013, China
| | - Pei-Bei Sun
- Department of Reproductive Physiology, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013, China
| | - Xiao-Liang Zheng
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013, China
| | - Xiao-Ju Wang
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013; Institute of Lung Cancer, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013, China
| |
Collapse
|
|
32
|
Mims AS, Mishra A, Orwick S, Blachly J, Klisovic RB, Garzon R, Walker AR, Devine SM, Walsh KJ, Vasu S, Whitman S, Marcucci G, Jones D, Heerema NA, Lozanski G, Caligiuri MA, Bloomfield CD, Byrd JC, Piekarz R, Grever MR, Blum W. A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485. Haematologica 2018; 103:982-987. [PMID: 29567781 PMCID: PMC6058798 DOI: 10.3324/haematol.2017.186890] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 03/21/2017] [Indexed: 12/29/2022] Open
Abstract
KMT2A partial tandem duplication occurs in approximately 5–10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1–10 and vorinostat 400 milligrams daily on days 5–10. Cytarabine was dose-escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506).
Collapse
Affiliation(s)
- Alice S Mims
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Anjali Mishra
- Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Shelley Orwick
- Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - James Blachly
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Rebecca B Klisovic
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA
| | - Ramiro Garzon
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Alison R Walker
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Steven M Devine
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Katherine J Walsh
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Sumithira Vasu
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Susan Whitman
- Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Guido Marcucci
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
| | - Daniel Jones
- Department of Pathology, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Nyla A Heerema
- Department of Pathology, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Gerard Lozanski
- Department of Pathology, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Michael A Caligiuri
- Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Clara D Bloomfield
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - John C Byrd
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Richard Piekarz
- Investigational Drug Branch of CTEP, National Cancer Institute, Bethesda, MD, USA
| | - Michael R Grever
- Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - William Blum
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA
| |
Collapse
|
|
33
|
Sun Y, Chen BR, Deshpande A. Epigenetic Regulators in the Development, Maintenance, and Therapeutic Targeting of Acute Myeloid Leukemia. Front Oncol 2018. [PMID: 29527516 PMCID: PMC5829038 DOI: 10.3389/fonc.2018.00041] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The importance of epigenetic dysregulation to acute myeloid leukemia (AML) pathophysiology has become increasingly apparent in recent years. Epigenetic regulators, including readers, writers, and erasers, are recurrently dysregulated by way of chromosomal translocations, somatic mutations, or genomic amplification in AML and many of these alterations are directly implicated in AML pathogenesis. Mutations in epigenetic regulators are often discovered in founder clones and persist after therapy, indicating that they may contribute to a premalignant state poised for the acquisition of cooperating mutations and frank malignancy. Apart from the proto-oncogenic impact of these mutations, the AML epigenome is also shaped by other epigenetic factors that are not mutated but co-opted by AML oncogenes, presenting with actionable vulnerabilities in this disease. Targeting the AML epigenome might also be important for eradicating AML leukemia stem cells, which can be critical for disease maintenance and resistance to therapy. In this review, we describe the importance of epigenetic regulators in AML. We also summarize evidence implicating specific epigenetic regulators in AML pathobiology and discuss emerging epigenome-based therapies for the treatment of AML in the clinic.
Collapse
Affiliation(s)
- Younguk Sun
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Bo-Rui Chen
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Aniruddha Deshpande
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| |
Collapse
|
|
34
|
Qin YZ, Zhao T, Zhu HH, Wang J, Jia JS, Lai YY, Zhao XS, Shi HX, Liu YR, Jiang H, Huang XJ, Jiang Q. High EVI1 Expression Predicts Poor Outcomes in Adult Acute Myeloid Leukemia Patients with Intermediate Cytogenetic Risk Receiving Chemotherapy. Med Sci Monit 2018; 24:758-767. [PMID: 29408852 PMCID: PMC5810369 DOI: 10.12659/msm.905903] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 08/30/2017] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Acute myeloid leukemia with intermediate cytogenetic risk (ICR-AML) needs to be stratified. The abnormal gene expression might be prognostic, and its cutoff value for patient grouping is pivotal. MATERIAL AND METHODS Ecotropic viral integration site 1 (EVI1) transcripts were assessed in 191 adult ICR-AML patients at diagnosis who received chemotherapy only. MLL-PTD, WT1 transcript levels, FLT3-ITD, and NPM1 mutations were simultaneously evaluated, and 27 normal bone marrow samples were tested to define normal threshold. RESULTS The normal upper limit of EVI1 transcript levels was 8.0%. Receiver operating characteristic curve analysis showed that 1.0% (a 0.9-log reduction from the normal limit) was the EVI1 optimal cutoff value for significantly differentiating relapse (P=0.049). A total of 23 patients (12%) had EVI1 levels ≥1.0%. EVI1 ≥1.0% had no effect on CR achievement, whereas it was significantly associated with lower 2-year relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS) rates in the entire cohort (P=0.0003, 0.0017, and 0.0009, respectively), patients with normal karyotypes (P=0.0032, 0.0047, and 0.0007, respectively), and FLT3-ITD (-) patients (all P<0.0001). Multivariate analysis showed that EVI1 ≥1.0% was an independent adverse prognostic factor for RFS, DFS, and OS in the entire cohort. In addition, patients with EVI1 transcript levels between 1.0% and 8.0% had 2-year RFS rates similar to those with EVI1 ≥8.0%, and they both had significantly lower RFS rates than those with EVI1 <1.0% (P=0.0005 and 0.027). CONCLUSIONS High EVI1 expression predicts poor outcome in ICR-AML patients receiving chemotherapy. The optimal cutoff value for patient stratification is different from the normal limit.
Collapse
|
|
35
|
Choi SM, Dewar R, Burke PW, Shao L. Partial tandem duplication of KMT2A (MLL) may predict a subset of myelodysplastic syndrome with unique characteristics and poor outcome. Haematologica 2018; 103:e131-e134. [PMID: 29351983 DOI: 10.3324/haematol.2017.185249] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
- Sarah M Choi
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Rajan Dewar
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Patrick W Burke
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Lina Shao
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| |
Collapse
|
|
36
|
Aziz H, Ping CY, Alias H, Ab Mutalib NS, Jamal R. Gene Mutations as Emerging Biomarkers and Therapeutic Targets for Relapsed Acute Myeloid Leukemia. Front Pharmacol 2017; 8:897. [PMID: 29270125 PMCID: PMC5725465 DOI: 10.3389/fphar.2017.00897] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 11/24/2017] [Indexed: 12/19/2022] Open
Abstract
It is believed that there are key differences in the genomic profile between adult and childhood acute myeloid leukemia (AML). Relapse is the significant contributor of mortality in patients with AML and remains as the leading cause of cancer death among children, posing great challenges in the treatment of AML. The knowledge about the genomic lesions in childhood AML is still premature as most genomic events defined in children were derived from adult cohorts. However, the emerging technologies of next generation sequencing have narrowed the gap of knowledge in the biology of AML by the detection of gene mutations for each sub-type which have led to the improvement in terms of prognostication as well as the use of targeted therapies. In this review, we describe the recent understanding of the genomic landscape including the prevalence of mutation, prognostic impact, and targeted therapies that will provide an insight into the pathogenesis of AML relapse in both adult and childhood cases.
Collapse
Affiliation(s)
- Habsah Aziz
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Chow Y Ping
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Hamidah Alias
- Department of Paediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | | | - Rahman Jamal
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| |
Collapse
|
|
37
|
|
|
38
|
McCurdy SR, Levis MJ. Emerging molecular predictive and prognostic factors in acute myeloid leukemia. Leuk Lymphoma 2017; 59:2021-2039. [DOI: 10.1080/10428194.2017.1393669] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Shannon R. McCurdy
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mark J. Levis
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
39
|
Zhang H, Zhang C, Feng R, Zhang H, Gao M, Ye L. Investigating the microRNA-mRNA regulatory network in acute myeloid leukemia. Oncol Lett 2017; 14:3981-3988. [PMID: 28989535 PMCID: PMC5620483 DOI: 10.3892/ol.2017.6686] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 05/25/2017] [Indexed: 12/26/2022] Open
Abstract
Acute myeloid leukemia (AML) is a common myelogenous malignancy in adults that is often characterized by disease relapse. The pathophysiological mechanism of AML has not yet been elucidated. The present study aimed to identify the crucial microRNAs (miRNAs/miRs) and target genes in AML, and to uncover the potential oncogenic mechanism of AML. miRNA and mRNA expression-profiling microarray datasets were downloaded from the Gene Expression Omnibus database. Differential expression analysis was performed and a regulatory network between miRNAs and target genes was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were used to predict the biological functions of the differentially expressed genes. Reverse transcription-quantitative polymerase chain reaction analysis was employed to verify the expression levels of miRNAs and target genes in AML patient samples. A total of 86 differentially expressed miRNAs and 468 differentially expressed mRNAs between AML and healthy blood samples were identified. In total, 47 miRNAs and 401 mRNAs were found to be upregulated, and 39 miRNAs and 67 mRNAs were found to be downregulated in AML. A total of 223 miRNA-target genes pairs were subjected to the construction of a regulatory network. Differentially expressed target genes were significantly enriched in the Wnt signaling pathway (hsa04310), melanogenesis (hsa04916) and pathways in cancer (hsa05200). Significantly differentially expressed miRNAs and genes, including hsa-miR-155, hsa-miR-192, annexin A2 (ANXA2), frizzled class receptor 3 (FZD3), and pleomorphic adenoma gene 1 (PLAG1), may serve essential roles in AML oncogenesis. Overall, hsa-miR-155, hsa-miR-192, ANXA2, FZD3 and PLAG1 may be associated with the development of AML via the involvement of the Wnt signaling pathway, melanogenesis and other cancer-associated signaling pathways.
Collapse
Affiliation(s)
- Haiguo Zhang
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
- Department of Hematology, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Chengfang Zhang
- Department of Clinical Laboratory, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Rui Feng
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
- Department of Hematology, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Haixia Zhang
- Department of Pharmacy, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Min Gao
- Department of Clinical Laboratory, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Ling Ye
- Department of Hematology, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| |
Collapse
|
|
40
|
Kong J, Zhao XS, Qin YZ, Zhu HH, Jia JS, Jiang Q, Wang J, Zhao T, Huang XJ, Jiang H. The initial level of MLL-partial tandem duplication affects the clinical outcomes in patients with acute myeloid leukemia. Leuk Lymphoma 2017; 59:967-972. [PMID: 28745571 DOI: 10.1080/10428194.2017.1352091] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Jun Kong
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| | - Xiao-Su Zhao
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| | - Ya-Zhen Qin
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| | - Hong-Hu Zhu
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| | - Jin-Song Jia
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| | - Qian Jiang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| | - Jing Wang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| | - Ting Zhao
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| | - Xiao-Jun Huang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| | - Hao Jiang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Institute of Hematology, Beijing, People’s Republic of China
| |
Collapse
|
|
41
|
Abstract
Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, standard treatment options have not significantly changed during the past three decades. AML is characterized by multiple somatically acquired mutations that affect genes of different functional categories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. By contrast, mutations involving NPM1 or signalling molecules (e.g., FLT3, RAS gene family) are typically secondary events that occur later during leukaemogenesis. This review aims to provide an overview of advances in new prognostic markers, including targetable mutations that will probably guide the development and use of novel molecularly targeted therapies.
Collapse
Affiliation(s)
- Michael Medinger
- Division of Haematology, University Hospital Basel, Basel, Switzerland.,Division of Internal Medicine, University Hospital Basel, Basel, Switzerland
| | - Jakob R Passweg
- Division of Haematology, University Hospital Basel, Basel, Switzerland
| |
Collapse
|
|
42
|
Malek R, Gajula RP, Williams RD, Nghiem B, Simons BW, Nugent K, Wang H, Taparra K, Lemtiri-Chlieh G, Yoon AR, True L, An SS, DeWeese TL, Ross AE, Schaeffer EM, Pienta KJ, Hurley PJ, Morrissey C, Tran PT. TWIST1-WDR5- Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis. Cancer Res 2017; 77:3181-3193. [PMID: 28484075 DOI: 10.1158/0008-5472.can-16-2797] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 03/03/2017] [Accepted: 04/19/2017] [Indexed: 12/22/2022]
Abstract
TWIST1 is a transcription factor critical for development that can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are coexpressed in mouse prostate and then silenced postnatally. Here we report that TWIST1 and HOXA9 coexpression are reactivated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS-like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development. TWIST1 overexpression led to coenrichment of TWIST1 and WDR5 as well as increased H3K4me3 chromatin at the Hoxa9/HOXA9 promoter, which was dependent on WDR5. Expression of WDR5 and Hottip/HOTTIP was also required for TWIST1-induced upregulation of HOXA9 and aggressive cellular phenotypes such as invasion and migration. Pharmacologic inhibition of HOXA9 prevented TWIST1-induced aggressive prostate cancer cellular phenotypes in vitro and metastasis in vivo This study demonstrates a novel mechanism by which TWIST1 regulates chromatin and gene expression by cooperating with the COMPASS-like complex to increase H3K4 trimethylation at target gene promoters. Our findings highlight a TWIST1-HOXA9 embryonic prostate developmental program that is reactivated during prostate cancer metastasis and is therapeutically targetable. Cancer Res; 77(12); 3181-93. ©2017 AACR.
Collapse
Affiliation(s)
- Reem Malek
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Rajendra P Gajula
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Russell D Williams
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Belinda Nghiem
- Department of Urology, University of Washington, Seattle, Washington
| | - Brian W Simons
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Katriana Nugent
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hailun Wang
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kekoa Taparra
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ghali Lemtiri-Chlieh
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Arum R Yoon
- Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
| | - Lawrence True
- Department of Pathology, University of Washington, Seattle, Washington
| | - Steven S An
- Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.,Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland
| | - Theodore L DeWeese
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ashley E Ross
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Edward M Schaeffer
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kenneth J Pienta
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Paula J Hurley
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Colm Morrissey
- Department of Urology, University of Washington, Seattle, Washington
| | - Phuoc T Tran
- Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. .,Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
43
|
Molecular Mutations and Their Cooccurrences in Cytogenetically Normal Acute Myeloid Leukemia. Stem Cells Int 2017; 2017:6962379. [PMID: 28197208 PMCID: PMC5288537 DOI: 10.1155/2017/6962379] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 12/25/2016] [Indexed: 01/08/2023] Open
Abstract
Adult acute myeloid leukemia (AML) clinically is a disparate disease that requires intensive treatments ranging from chemotherapy alone to allogeneic hematopoietic cell transplantation (allo-HCT). Historically, cytogenetic analysis has been a useful prognostic tool to classify patients into favorable, intermediate, and unfavorable prognostic risk groups. However, the intermediate-risk group, consisting predominantly of cytogenetically normal AML (CN-AML), itself exhibits diverse clinical outcomes and requires further characterization to allow for more optimal treatment decision-making. The recent advances in clinical genomics have led to the recategorization of CN-AML into favorable or unfavorable subgroups. The relapsing nature of AML is thought to be due to clonal heterogeneity that includes founder or driver mutations present in the leukemic stem cell population. In this article, we summarize the clinical outcomes of relevant molecular mutations and their cooccurrences in CN-AML, including NPM1, FLT3ITD, DNMT3A, NRAS, TET2, RUNX1, MLLPTD, ASXL1, BCOR, PHF6, CEBPAbiallelic, IDH1, IDH2R140, and IDH2R170, with an emphasis on their relevance to the leukemic stem cell compartment. We have reviewed the available literature and TCGA AML databases (2013) to highlight the potential role of stem cell regulating factor mutations on outcome within newly defined AML molecular subgroups.
Collapse
|
|
44
|
Pastore F, Levine RL. Epigenetic regulators and their impact on therapy in acute myeloid leukemia. Haematologica 2017; 101:269-78. [PMID: 26928248 DOI: 10.3324/haematol.2015.140822] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Genomic studies of hematologic malignancies have identified a spectrum of recurrent somatic alterations that contribute to acute myeloid leukemia initiation and maintenance, and which confer sensitivities to molecularly targeted therapies. The majority of these genetic events are small, site-specific alterations in DNA sequence. In more than two thirds of patients with de novo acute myeloid leukemia mutations epigenetic modifiers are detected. Epigenetic modifiers encompass a large group of proteins that modify DNA at cytosine residues or cause post-translational histone modifications such as methylations or acetylations. Altered functions of these epigenetic modifiers disturb the physiological balance between gene activation and gene repression and contribute to aberrant gene expression regulation found in acute myeloid leukemia. This review provides an overview of the epigenetic modifiers mutated in acute myeloid leukemia, their clinical relevance and how a deeper understanding of their biological function has led to the discovery of new specific targets, some of which are currently tested in mechanism-based clinical trials.
Collapse
Affiliation(s)
- Friederike Pastore
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
| | - Ross L Levine
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| |
Collapse
|
|
45
|
Winters AC, Bernt KM. MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches. Front Pediatr 2017; 5:4. [PMID: 28232907 PMCID: PMC5299633 DOI: 10.3389/fped.2017.00004] [Citation(s) in RCA: 284] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 01/09/2017] [Indexed: 12/18/2022] Open
Abstract
The mixed-lineage leukemia 1 (MLL1) gene (now renamed Lysine [K]-specific MethylTransferase 2A or KMT2A) on chromosome 11q23 is disrupted in a unique group of acute leukemias. More than 80 different partner genes in these fusions have been described, although the majority of leukemias result from MLL1 fusions with one of about six common partner genes. Approximately 10% of all leukemias harbor MLL1 translocations. Of these, two patient populations comprise the majority of cases: patients younger than 1 year of age at diagnosis (primarily acute lymphoblastic leukemias) and young- to-middle-aged adults (primarily acute myeloid leukemias). A much rarer subgroup of patients with MLL1 rearrangements develop leukemia that is attributable to prior treatment with certain chemotherapeutic agents-so-called therapy-related leukemias. In general, outcomes for all of these patients remain poor when compared to patients with non-MLL1 rearranged leukemias. In this review, we will discuss the normal biological roles of MLL1 and its fusion partners, how these roles are hypothesized to be dysregulated in the context of MLL1 rearrangements, and the clinical manifestations of this group of leukemias. We will go on to discuss the progress in clinical management and promising new avenues of research, which may lead to more effective targeted therapies for affected patients.
Collapse
Affiliation(s)
- Amanda C Winters
- Division of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado , Aurora, CO , USA
| | - Kathrin M Bernt
- Division of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado , Aurora, CO , USA
| |
Collapse
|
|
46
|
Frontline treatment of acute myeloid leukemia in adults. Crit Rev Oncol Hematol 2016; 110:20-34. [PMID: 28109402 DOI: 10.1016/j.critrevonc.2016.12.004] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 11/01/2016] [Accepted: 12/07/2016] [Indexed: 01/13/2023] Open
Abstract
Recent years have highlighted significant progress in understanding the underlying genetic and epigenetic signatures of acute myeloid leukemia(AML). Most importantly, novel chemotherapy and targeted strategies have led to improved outcomes in selected genetic subsets. AML is a remarkably heterogeneous disease, and individualized therapies for disease-specific characteristics (considering patients' age, cytogenetics, and mutations) could yield better outcomes. Compared with the historical 5-to 10-year survival rate of 10%, the survival of patients who undergo modern treatment approaches reaches up to 40-50%, and for specific subsets, the improvements are even more dramatic; for example, in acute promyelocytic leukemia, the use of all-trans retinoic acid and arsenic trioxide improved survival from 30 to 40% up to 80 to 90%. Similar progress has been documented in core-binding-factor-AML, with an increase in survival from 30% to 80% upon the use of high-dose cytarabine/fludarabine/granulocyte colony-stimulating factor combination regimens. AML treatment was also recently influenced by the discovery of the superiority of regimens with higher dose Ara-C and nucleoside analogues compared with the "7+3"regimen, with about a 20% improvement in overall survival. Despite these significant differences, most centers continue to use the "7+3" regimen, and greater awareness will improve the outcome. The discovery of targetable molecular abnormalities and recent studies of targeted therapies (gemtuzumab ozagomycin, FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and epigenetic therapies), future use of checkpoint inhibitors and other immune therapies such as chimeric antigen receptor T-cells, and maintenance strategies based on the minimal residual disease evaluation represent novel, exciting clinical leads aimed to improve AML outcomes in the near future.
Collapse
|
|
47
|
Kao HW, Liang DC, Kuo MC, Wu JH, Dunn P, Wang PN, Lin TL, Shih YS, Liang ST, Lin TH, Lai CY, Lin CH, Shih LY. High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis. Oncotarget 2016; 6:33217-25. [PMID: 26375248 PMCID: PMC4741760 DOI: 10.18632/oncotarget.5202] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 08/28/2015] [Indexed: 12/27/2022] Open
Abstract
The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML.
Collapse
Affiliation(s)
- Hsiao-Wen Kao
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - D Cherng Liang
- Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan
| | - Ming-Chung Kuo
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jin-Hou Wu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Po Dunn
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Po-Nan Wang
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Tung-Liang Lin
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yu-Shu Shih
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Sung-Tzu Liang
- Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan
| | - Tung-Huei Lin
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chen-Yu Lai
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chun-Hui Lin
- Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan
| | - Lee-Yung Shih
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| |
Collapse
|
|
48
|
Yang H, Huang S, Zhu CY, Gao L, Zhu HY, Lv N, Jing Y, Yu L. The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation Over Chemotherapy Alone in the Treatment of Acute Myeloid Leukemia Patients with Mixed Lineage Leukemia (MLL) Rearrangements. Med Sci Monit 2016; 22:2315-23. [PMID: 27373985 PMCID: PMC4941891 DOI: 10.12659/msm.899186] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) patients with mixed lineage leukemia (MLL) gene rearrangements always had a very poor prognosis. In this study, we report the incidence of MLL rearrangements in AML patients using gene analysis, as well as the clinical significance and prognostic features of these rearrangements. MATERIAL AND METHODS This retrospective study took place from April 2008 to November 2011 in the People's Liberation Army General Hospital. A total 433 AML patients were screened by multiple nested reverse transcription polymerase chain reaction (RT-PCR) to determine the incidence of the 11 MLL gene rearrangements. There were 68 cases of MLL gene rearrangements, for a positive rate of 15.7%. A total of 24 patients underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and 34 patients received at least 4 cycles of chemotherapy. Ten patients were lost to follow-up. RESULTS The median follow-up was 29 months. The complete remission (CR) rate was 85.4%. The overall survival (OS) was 57.4±5.9 months for the Allo-HSCT group and 21.0±2.1 months for the chemotherapy group. The Allo-HSCT group had superior survival compared with the chemotherapy group (5-year OS: 59±17% vs. 13±8%, P<0.01; 5-year disease-free survival [DFS]: 65±10% vs. 40±16%, P>0.05). Multivariate analysis showed that transplantation, platelets >50×10^9/L at onset, and CR are associated with a better OS in MLL rearranged AML patients. Patients with thrombocytopenia and extramedullary involvement were prone to relapse. CONCLUSIONS Our results suggest that Allo-HSCT is superior to chemotherapy alone for treating MLL rearranged AML patients. Patients treated with Allo-HSCT have a better prognosis and a longer survival. CR is an independent prognostic factor for OS, and extramedullary involvement is an independent prognostic factor for DFS. MLL rearranged AML patients with thrombocytopenia at onset <50×10^9 had very bad OS and DFS.
Collapse
Affiliation(s)
- Hua Yang
- Department of Hematology and BMT, Chinese PLA General Hospital, Beijing, China (mainland)
| | - Sai Huang
- Department of Hematology and BMT, Chinese PLA General Hospital, Beijing, China (mainland)
| | - Cheng-Ying Zhu
- Department of Hematology and BMT, Chinese PLA General Hospital, Beijing, China (mainland)
| | - Li Gao
- Department of Hematology and BMT, Chinese PLA General Hospital, Beijing, China (mainland)
| | - Hai-Yan Zhu
- Department of Hematology and BMT, Chinese PLA General Hospital, Beijing, China (mainland)
| | - Na Lv
- Department of Hematology and BMT, Chinese PLA General Hospital, Beijing, China (mainland)
| | - Yu Jing
- Department of Hematology and BMT, Chinese PLA General Hospital, Beijing, China (mainland)
| | - Li Yu
- Department of Hematology and BMT, Chinese PLA General Hospital, Beijing, China (mainland)
| |
Collapse
|
|
49
|
Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD). Leukemia 2016; 31:1-10. [PMID: 27389053 PMCID: PMC5214979 DOI: 10.1038/leu.2016.160] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 05/21/2016] [Accepted: 05/25/2016] [Indexed: 12/22/2022]
Abstract
Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.
Collapse
|
|
50
|
Hyrenius-Wittsten A, Sturesson H, Bidgoli M, Jonson T, Ehinger M, Lilljebjörn H, Scheding S, Andersson AK. Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia. Genes Chromosomes Cancer 2016; 55:847-54. [PMID: 27240832 DOI: 10.1002/gcc.22384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 05/24/2016] [Accepted: 05/24/2016] [Indexed: 12/19/2022] Open
Abstract
Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are rare genetically heterogeneous hematologic diseases associated with older age and a poor prognosis. If the disease progresses into acute myeloid leukemia (AML), it is often refractory to treatment. To gain insight into genetic alterations associated with disease progression, whole exome sequencing and single nucleotide polymorphism arrays were used to characterize the bone marrow and blood samples from a 39-year-old woman at MDS/MPN-U diagnosis and at AML progression, in which routine genetic diagnostics had not identified any genetic alterations. The data revealed the presence of a partial tandem duplication of the MLL gene as the only detectable copy number change and 11 non-silent somatic mutations, including DNMT3A R882H and NRAS G13D. All somatic lesions were present both at initial MDS/MPN-U diagnosis and at AML presentation at similar mutant allele frequencies. The patient has since had two extramedullary relapses and is at high risk of a future bone marrow relapse. A directed ex vivo drug sensitivity analysis showed that the patient's AML cells are sensitive to, for example, the MEK inhibitor trametinib and the proteasome inhibitor bortezomib, indicating that she may benefit from treatment with these drugs. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Axel Hyrenius-Wittsten
- Faculty of Medicine, Department of Laboratory Medicine Lund, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Helena Sturesson
- Faculty of Medicine, Department of Laboratory Medicine Lund, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Mahtab Bidgoli
- Department of Clinical Genetics, Lund University, Skane University Hospital, Lund, Sweden
| | - Tord Jonson
- Department of Clinical Genetics, Lund University, Skane University Hospital, Lund, Sweden
| | - Mats Ehinger
- Department of Pathology, Lund University, Skane University Hospital, Lund, Sweden
| | - Henrik Lilljebjörn
- Faculty of Medicine, Department of Laboratory Medicine Lund, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Stefan Scheding
- Faculty of Medicine, Department of Laboratory Medicine Lund, Lund Stem Cell Center, Lund University, Lund, Sweden.,Department of Hematology, Lund University, Skane University Hospital, Lund, Sweden
| | - Anna K Andersson
- Faculty of Medicine, Department of Laboratory Medicine Lund, Division of Clinical Genetics, Lund University, Lund, Sweden.
| |
Collapse
|