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Rao J, Kirk PDW. VICatMix: variational Bayesian clustering and variable selection for discrete biomedical data. BIOINFORMATICS ADVANCES 2025; 5:vbaf055. [PMID: 40206332 PMCID: PMC11981716 DOI: 10.1093/bioadv/vbaf055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Accepted: 03/13/2025] [Indexed: 04/11/2025]
Abstract
Summary Effective clustering of biomedical data is crucial in precision medicine, enabling accurate stratification of patients or samples. However, the growth in availability of high-dimensional categorical data, including 'omics data, necessitates computationally efficient clustering algorithms. We present VICatMix, a variational Bayesian finite mixture model designed for the clustering of categorical data. The use of variational inference (VI) in its training allows the model to outperform competitors in terms of computational time and scalability, while maintaining high accuracy. VICatMix furthermore performs variable selection, enhancing its performance on high-dimensional, noisy data. The proposed model incorporates summarization and model averaging to mitigate poor local optima in VI, allowing for improved estimation of the true number of clusters simultaneously with feature saliency. We demonstrate the performance of VICatMix with both simulated and real-world data, including applications to datasets from The Cancer Genome Atlas, showing its use in cancer subtyping and driver gene discovery. We demonstrate VICatMix's potential utility in integrative cluster analysis with different 'omics datasets, enabling the discovery of novel disease subtypes. Availability and implementation VICatMix is freely available as an R package via CRAN, incorporating C++ for faster computation, at https://CRAN.R-project.org/package=VICatMix.
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Affiliation(s)
- Jackie Rao
- MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, United Kingdom
| | - Paul D W Kirk
- MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, United Kingdom
- CRUK Cambridge Centre Ovarian Programme, University of Cambridge, Cambridge, CB2 0RE, United Kingdom
- Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, CB2 0AW, United Kingdom
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2
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Iravani Saadi M, Moayedi J, Hosseini F, Rostamipour HA, Karimi Z, Rahimian Z, Ahmadyan M, Ghahramani Z, Dehghani M, Yousefi K, Kheradmand N, Ramzi M, Fooladivanda N. The Effects of Resveratrol, Gallic Acid, and Piperine on the Expression of miR-17, miR-92b, miR-181a, miR-222, BAX, BCL-2, MCL-1, WT1, c-Kit, and CEBPA in Human Acute Myeloid Leukemia Cells and Their Roles in Apoptosis. Biochem Genet 2024; 62:2958-2974. [PMID: 38062274 DOI: 10.1007/s10528-023-10582-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/28/2023] [Indexed: 07/31/2024]
Abstract
MicroRNAs (miRs) play a crucial role in the leukemogenesis and the prognosis of acute myeloid leukemia (AML). This study investigated the therapeutic effects of resveratrol, gallic acid, and piperine as natural anticancer agents on the HL-60 cell line and their roles in apoptosis. In this experimental study, quantitative analysis of miRs, including miR-17, miR-92b, miR-181a, and miR-222, were performed in 150 newly diagnosed patients with AML by real-time PCR assay. HL-60 cell viability as well as the expression of miRs, BAX, BCL-2, MCL-1, WT1, c-Kit, and CEBPA, were also assessed after transfection with the LNA-miRs and treatment with resveratrol, gallic acid, and piperine. The expression of miR-17 and miR-181a decreased significantly in LNA-anti-miRs. Although HL-60 cell viability decreased in LNA-anti-miR-222, miR-17, and miR-92b, blockade of miR-181a increased the cell viability. Besides, the cell viability increased merely in the piperine-treated group. Compared to untreated cells, miR-17 and miR-92b expression significantly increased in gallic acid- and resveratrol-treated cells. In HL-60 cells treated with resveratrol, gallic acid, and piperine, the expression of miR-181a was also increased significantly. The expression of BAX was also increased in resveratrol and piperine-treated groups. Compared to untreated cells, the expression of c-Kit increased significantly in the piperine-treated group; however, it decreased in the resveratrol-treated group. LNA-anti-miRs may be a promising agent for the treatment of AML. All three compounds used in this study showed anticancer effects, which can exert the desired outcome in patients with AML.
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Affiliation(s)
| | - Javad Moayedi
- Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fakhroddin Hosseini
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Zahed Karimi
- Hormozgan University of Medical Sciences, Bandar Abbas, Hormozgan, Iran
| | - Zahra Rahimian
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Ahmadyan
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Ghahramani
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehdi Dehghani
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Hematology, Oncology and Bone Marrow Transplantation Department, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Karim Yousefi
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nadiya Kheradmand
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mani Ramzi
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Hematology, Oncology and Bone Marrow Transplantation Department, Shiraz University of Medical Sciences, Shiraz, Iran.
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Fei F, Caporale C, Chang L, Fortini BK, Ali H, Bell D, Stein A, Marcucci G, Telatar M, Afkhami M. BRAF Mutations in Patients with Myeloid Neoplasms: A Cancer Center Multigene Next-Generation Sequencing Analysis Experience. Int J Mol Sci 2024; 25:5183. [PMID: 38791222 PMCID: PMC11121641 DOI: 10.3390/ijms25105183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/01/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
BRAF mutations are rare in myeloid neoplasms and are reported to be associated with poor treatment outcomes. The purpose of our study is to characterize BRAF mutations in myeloid neoplasms using a next-generation sequencing (NGS) panel based on the experiences of a single cancer center. We conducted a retrospective review of patients with myeloid neoplasms who underwent the HopeSeq studies between January 2018 and September 2023. A total of 14 patients with myeloid neoplasms carrying BRAF mutations were included in our cohort. The clinical, pathological, and molecular features of these patients were investigated. Our study indicates that BRAF mutations are rare in myeloid neoplasms, constituting only 0.53% (14/2632) of all myeloid neoplasm cases, with the most common BRAF mutation being BRAF V600E (4/14; 28.6%). Interestingly, we observed that six out of seven patients with acute myeloid leukemia (AML) exhibited AML with monocytic differentiation, and all the patients with AML exhibited an extremely poor prognosis compared to those without BRAF mutations. TET2 (5/14; 35.7%), ASXL1 (4/14; 28.6%), and JAK2 (4/14; 28.6%) were the three most frequently co-mutated genes in these patients. Moreover, we noted concurrent KMT2A gene rearrangement with BRAF mutations in three patients with AML (3/7; 42.9%). Our study suggests that although BRAF mutations are rare in myeloid neoplasms, they play a crucial role in the pathogenesis of specific AML subtypes. Furthermore, RAS pathway alterations, including BRAF mutations, are associated with KMT2A gene rearrangement in AML. However, these findings warrant further validation in larger studies.
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Affiliation(s)
- Fei Fei
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (F.F.)
| | - Caitlin Caporale
- Breast Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;
| | - Lisa Chang
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (F.F.)
| | | | - Haris Ali
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Diana Bell
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
| | - Anthony Stein
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Guido Marcucci
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Milhan Telatar
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (F.F.)
| | - Michelle Afkhami
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (F.F.)
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Morris VS, Ghazi H, Fletcher DM, Guinn BA. A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis. Int J Mol Sci 2023; 24:9667. [PMID: 37298623 PMCID: PMC10253696 DOI: 10.3390/ijms24119667] [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: 04/26/2023] [Revised: 05/27/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies with age with associated differences in incidence, as well as the frequency of cytogenetic change and somatic mutations. In addition, 5-year survival rates in paediatrics are 60-75% but fall to 5-15% in older AML patients. This systematic review aimed to determine whether the altered genes in AML affect the same molecular pathways, indifferent of patient age, and, therefore, whether patients could benefit from the repurposing drugs or the use of the same immunotherapeutic strategies across age boundaries to prevent relapse. Using a PICO framework and PRISMA-P checklist, relevant publications were identified using five literature databases and assessed against an inclusion criteria, leaving 36 articles, and 71 targets for therapy, for further analysis. QUADAS-2 was used to determine the risk of bias and perform a quality control step. We then priority-ranked the list of cancer antigens based on predefined and pre-weighted objective criteria as part of an analytical hierarchy process used for dealing with complex decisions. This organized the antigens according to their potential to act as targets for the immunotherapy of AML, a treatment that offers an opportunity to remove residual leukaemia cells at first remission and improve survival rates. It was found that 80% of the top 20 antigens identified in paediatric AML were also within the 20 highest scoring immunotherapy targets in adult AML. To analyse the relationships between the targets and their link to different molecular pathways, PANTHER and STRING analyses were performed on the 20 highest scoring immunotherapy targets for both adult and paediatric AML. There were many similarities in the PANTHER and STRING results, including the most prominent pathways being angiogenesis and inflammation mediated by chemokine and cytokine signalling pathways. The coincidence of targets suggests that the repurposing of immunotherapy drugs across age boundaries could benefit AML patients, especially when used in combination with conventional therapies. However, due to cost implications, we would recommend that efforts are focused on ways to target the highest scoring antigens, such as WT1, NRAS, IDH1 and TP53, although in the future other candidates may prove successful.
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Affiliation(s)
- Vanessa S. Morris
- Department of Chemistry and Biochemistry, University of Hull, Kingston upon Hull HU6 7RX, UK;
| | - Hanya Ghazi
- Hull York Medical School, University of Hull, Kingston upon Hull HU6 7RX, UK;
| | - Daniel M. Fletcher
- Centre for Biomedicine, Hull York Medical School, Kingston upon Hull HU6 7RX, UK;
| | - Barbara-ann Guinn
- Centre for Biomedicine, Hull York Medical School, Kingston upon Hull HU6 7RX, UK;
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The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes. Leukemia 2023; 37:593-605. [PMID: 36631623 PMCID: PMC9991918 DOI: 10.1038/s41375-023-01810-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 12/22/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). Thus, the identification and characterization of novel epigenetic drivers affecting AML biology holds potential to improve our basic understanding of AML and to uncover novel options for therapeutic intervention. To identify novel tumor suppressive epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5C expression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpa mutant and inv(16) AML mouse models. Mechanistically, we show that KDM5C act as a transcriptional repressor through its demethylase activity at promoters. Specifically, KDM5C knockdown results in globally increased H3K4me3 levels associated with up-regulation of bivalently marked immature genes. This is accompanied by a de-differentiation phenotype that could be reversed by modulating levels of several direct and indirect downstream mediators. Finally, the association of KDM5C levels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.
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Rungjirajittranon T, Siriwannangkul T, Kungwankiattichai S, Leelakanok N, Rotchanapanya W, Vittayawacharin P, Mekrakseree B, Kulchutisin K, Owattanapanich W. Clinical Outcomes of Acute Myeloid Leukemia Patients Harboring the RUNX1 Mutation: Is It Still an Unfavorable Prognosis? A Cohort Study and Meta-Analysis. Cancers (Basel) 2022; 14:5239. [PMID: 36358658 PMCID: PMC9659296 DOI: 10.3390/cancers14215239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 08/05/2024] Open
Abstract
Acute myeloid leukemia (AML) with mutated RUNX1 (RUNX1mut) is considered to have an unfavorable prognosis. However, recent studies have reported comparable survival outcomes with wild-type RUNX1 (RUNX1wt). To assess the clinical outcomes of AML with and without RUNX1mut, we performed a prospective cohort study and systematic review and meta-analysis. The study enrolled 135 patients (27 with RUNX1mut; 108 with RUNX1wt). There were no significant differences in the median OS and RFS of the RUNX1mut and RUNX1wt groups (9.1 vs. 12.2 months; p = 0.268 and 7.8 vs. 14.6 months; p = 0.481, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics showed similar outcomes. Our meta-analysis pooled data from 23 studies and our study. The complete remission rate was significantly lower in the RUNX1mut group (pooled odds ratio: 0.42). The OS, RFS, and event-free survival rates also favored the RUNX1wt group (pooled risk ratios: 1.36, 1.37, and 1.37, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics demonstrated nearly identical OS and RFS outcomes. This study confirms that patients with AML and RUNX1mut had poor prognoses. Nonetheless, in de novo AML with intermediate-risk cytogenetics, the survival outcomes of both groups were comparable.
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Affiliation(s)
- Tarinee Rungjirajittranon
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Theerapat Siriwannangkul
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Smith Kungwankiattichai
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Nattawut Leelakanok
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Burapha University, Chonburi 20131, Thailand
| | | | - Pongthep Vittayawacharin
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | | | | | - Weerapat Owattanapanich
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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7
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Lit BMW, Guo BB, Malherbe JAJ, Kwong YL, Erber WN. Mutation profile of acute myeloid leukaemia in a Chinese cohort by targeted next-generation sequencing. Cancer Rep (Hoboken) 2021; 5:e1573. [PMID: 34617422 PMCID: PMC9575498 DOI: 10.1002/cnr2.1573] [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: 05/24/2021] [Revised: 08/10/2021] [Accepted: 08/23/2021] [Indexed: 11/07/2022] Open
Abstract
Background Acute myeloid leukaemia (AML) results from the clonal expansion of blast cells of myeloid origin driven by genomic defects. The advances in next‐generation sequencing (NGS) have allowed the identification of many mutated genes important in the pathogenesis of AML. Aims In this study, we aimed to assess the mutation types and frequency in a Chinese cohort presenting with de novo AML cohort using a targeted NGS strategy. Methods In total, we studied samples from 87 adult patients with de novo AML who had no prior history of cytotoxic chemotherapy. Samples were evaluated using a 120‐gene targeted NGS panel to assess the mutation profile. Results Of the 87 AML patients, there were 60 (69%) with a normal karyotype. 89.7% of patients had variants, with an average of 1.9 mutations per patient (range: 0–5 mutations per patient). DNMT3A variants were the most common, being detected in 33 patients (37.9%). NPM1 (34.5%), IDH1/2 (24.1%) and FLT3‐ITD (20.7%) mutations was the next most common. Of the patients with DNMT3A mutations, 24.2% also had mutations NPM1 and FLT3‐ITD and 6.1% NPM1, FLT3‐ITD and IDH mutations. Conclusion Both DNMT3A and NPM1 mutations were more common than in other Chinese and Western AML cohorts that have been studied. DNMT3A mutations tended to co‐occur with NPM1 and FLT3‐ITD mutations and were most commonly seen with a normal karyotype.
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Affiliation(s)
| | - Belinda B Guo
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
| | | | - Yok Lam Kwong
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Wendy N Erber
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia.,PathWest Laboratory Medicine, Nedlands, WA, Australia
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Yoon J, Cho EH, Yun JW, Kim HY, Jang JH, Kim HJ, Kim SH. LSAMP Rearrangement in Acute Myeloid Leukemia With a Jumping Translocation Involving 3q13.31. Ann Lab Med 2021; 41:342-345. [PMID: 33303723 PMCID: PMC7748089 DOI: 10.3343/alm.2021.41.3.342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 07/15/2020] [Accepted: 11/11/2020] [Indexed: 11/22/2022] Open
Affiliation(s)
- Jung Yoon
- Department of Laboratory Medicine, Korea University Guro Hospital, Seoul, Korea
| | - Eun Hye Cho
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Won Yun
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Korea
| | - Hyun-Young Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jun Ho Jang
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee-Jin Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sun-Hee Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Nie Y, Su L, Li W, Gao S. Novel insights of acute myeloid leukemia with CEBPA deregulation: Heterogeneity dissection and re-stratification. Crit Rev Oncol Hematol 2021; 163:103379. [PMID: 34087345 DOI: 10.1016/j.critrevonc.2021.103379] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 03/21/2021] [Accepted: 05/29/2021] [Indexed: 12/17/2022] Open
Abstract
Acute myeloid leukemia with bi-allelic CEBPA mutation was categorized as an independent disease entity with favorable prognosis, however, recent researches have revealed huge heterogeneity within this disease group, and for some patients, relapse remained a major cause of treatment failure. Further risk stratification is essentially needed. Here by reviewing the latest literature, we summarized the characteristics of CEBPA mutation profiles and clinical features, with a special intention of dissecting the heterogeneity within the seemingly homogeneous AML with bi-allelic CEBPA mutations. Specifically, non-classical CEBPA mutation, miscellaneous companion genetic aberrations and the presence of germline CEBPA mutation are three major sources of heterogeneity. Identifying these factors can help us predict patients at a higher risk of relapse, for whom aggressive treatment may be recommended. Novel therapeutic approaches regarding manipulating potentially druggable targets as well as the debate over post remission consolidation regimens has also been discussed.
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Affiliation(s)
- Yuanyuan Nie
- Department of Hematology, The First Hospital of Jilin University, Changchun, 130012, China
| | - Long Su
- Department of Hematology, The First Hospital of Jilin University, Changchun, 130012, China
| | - Wei Li
- Department of Hematology, The First Hospital of Jilin University, Changchun, 130012, China; Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, 130012, China
| | - Sujun Gao
- Department of Hematology, The First Hospital of Jilin University, Changchun, 130012, China.
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Papuc SM, Erbescu A, Cisleanu D, Ozunu D, Enache C, Dumitru I, Lupoaia Andrus E, Gaman M, Popov VM, Dobre M, Stanca O, Angelescu S, Berbec N, Colita A, Vladareanu AM, Bumbea H, Arghir A. Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies. Genes (Basel) 2021; 12:genes12060846. [PMID: 34070898 PMCID: PMC8229708 DOI: 10.3390/genes12060846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 12/19/2022] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients; in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the NPM1 gene, followed by DNMT3A, FLT3 and NRAS. An unexpected co-occurrence of KMT2A translocation and DNMT3A-R882 was identified; alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.
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Affiliation(s)
- Sorina Mihaela Papuc
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (S.M.P.); (A.E.); (D.O.); (M.D.)
| | - Alina Erbescu
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (S.M.P.); (A.E.); (D.O.); (M.D.)
| | - Diana Cisleanu
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Emergency Universitary Clinical Hospital, 050098 Bucharest, Romania;
| | - Diana Ozunu
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (S.M.P.); (A.E.); (D.O.); (M.D.)
| | - Cristina Enache
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Emergency Universitary Clinical Hospital, 050098 Bucharest, Romania;
| | - Ion Dumitru
- Emergency Universitary Clinical Hospital, 050098 Bucharest, Romania;
| | - Elena Lupoaia Andrus
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Emergency Universitary Clinical Hospital, 050098 Bucharest, Romania;
| | - Mihaela Gaman
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Emergency Universitary Clinical Hospital, 050098 Bucharest, Romania;
| | | | - Maria Dobre
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (S.M.P.); (A.E.); (D.O.); (M.D.)
| | - Oana Stanca
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Coltea Clinical Hospital, 030167 Bucharest, Romania
| | - Silvana Angelescu
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Coltea Clinical Hospital, 030167 Bucharest, Romania
| | - Nicoleta Berbec
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Coltea Clinical Hospital, 030167 Bucharest, Romania
| | - Andrei Colita
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Coltea Clinical Hospital, 030167 Bucharest, Romania
| | - Ana-Maria Vladareanu
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Emergency Universitary Clinical Hospital, 050098 Bucharest, Romania;
| | - Horia Bumbea
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.C.); (C.E.); (E.L.A.); (M.G.); (O.S.); (S.A.); (N.B.); (A.C.); (A.-M.V.); (H.B.)
- Emergency Universitary Clinical Hospital, 050098 Bucharest, Romania;
| | - Aurora Arghir
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (S.M.P.); (A.E.); (D.O.); (M.D.)
- Correspondence: ; Tel.: +40-2-1319-2732-207; Fax: +40-2-1319-4528
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Akram AM, Chaudhary A, Kausar H, Althobaiti F, Abbas AS, Hussain Z, Fatima N, Zafar E, Asif W, Afzal U, Yousaf Z, Zafar A, Harakeh SM, Qamer S. Analysis of RAS gene mutations in cytogenetically normal de novo acute myeloid leukemia patients reveals some novel alterations. Saudi J Biol Sci 2021; 28:3735-3740. [PMID: 34220225 PMCID: PMC8241590 DOI: 10.1016/j.sjbs.2021.04.089] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/20/2021] [Accepted: 04/28/2021] [Indexed: 11/26/2022] Open
Abstract
Rat sarcoma gene (RAS) holds great importance in pathogenesis of acute myeloid leukemia (AML). The activated mutations in Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) and Kirsten rat sarcoma viral oncogene homolog (KRAS) confers proliferative and survival signals, deliberating numerous effects on overall survival and progression free survival in AML patients. In this study thirty one (31) blood samples of adult newly diagnosed AML patients were collected to identify possible incidence of mutations through amplification of KRAS (exon 1 and 2) and NRAS gene (exon 1 and 2) using polymerase chain reaction (PCR). Amplicons were then subjected to sequencing and were analyzed through Geneious Prime 2019. Five of thirty one (16.12%) patients had altered sites in either NRAS or KRAS. The NRAS mutations were observed in three AML patients (N = 3, 9.67%). A novel missense mutation NRAS-I36R (239 T > G) representing a substitution of single nucleotide basepair found in NRAS exon 1 while exon 2 was detected with heterozygous mutation NRAS-E63X (318G > T) and insertion (A), resulting in frameshift of the amino acid sequence and insertion of two nucleotide basepairs (TA) in two of the patients. KRAS mutations (N = 2, 6.45%) were found in exon 1 whereas no mutations in KRAS exon 2 were detected in our patient cohort. Mutation in KRAS Exon 1, KRAS-D30N (280G > A) was observed in two patients and one of them also had a novel heterozygous mutation KRAS-L16N (240G > C). In addition there was no statistically significant association of mutRAS gene of AML patients with several prognostic markers including age, gender, karyotyping, CD34 positivity, cytogenetic abnormalities, total leukocyte count, white blood cell count and French-American-British (FAB) classification. However, the presence of mutRAS gene were strongly associated (p = 0.001) with increased percentage of bone marrow blasts. The prevalence of mutations in correlation with clinical and hematological parameter is useful for risk stratification in AML patients.
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Affiliation(s)
- Afia Muhammad Akram
- Department of Zoology, Division of Science and Technology, University of Education, Township, Lahore, Pakistan
| | - Asma Chaudhary
- Department of Zoology, Division of Science and Technology, University of Education, Township, Lahore, Pakistan
| | - Humera Kausar
- Department of Biotechnology, Kinnaird College for Women, Lahore, Pakistan
| | - Fayez Althobaiti
- Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Afshan Syed Abbas
- Department of Zoology, University of Education, Lower Mall Campus, Lahore, Pakistan
| | - Zawar Hussain
- Department of Zoology, Division of Science and Technology, University of Education, Township, Lahore, Pakistan
| | - Naz Fatima
- Molecular Biology Laboratory, Department of Zoology, University of the Punjab, Lahore, Pakistan
| | - Erum Zafar
- Department of Zoology, Division of Science and Technology, University of Education, Township, Lahore, Pakistan
| | - Wajiha Asif
- Department of Zoology, Division of Science and Technology, University of Education, Township, Lahore, Pakistan
| | - Umair Afzal
- Department of Zoology, Division of Science and Technology, University of Education, Township, Lahore, Pakistan
| | - Zoufishan Yousaf
- Department of Zoology, Division of Science and Technology, University of Education, Township, Lahore, Pakistan
| | - Amjad Zafar
- Department of Oncology, Mayo Hospital, Anarkali Bazar, Lahore, Pakistan
| | - Steve M Harakeh
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Samina Qamer
- Department of Zoology, Government College University, Faisalabad, Pakistan
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Zhou X, Friedlander S, Kupperman E, Sedarati F, Kuroda S, Hua Z, Yuan Y, Yamamoto Y, Faller DV, Haikawa K, Nakai K, Bowen S, Dai Y, Venkatakrishnan K. Asia-inclusive global development of pevonedistat: Clinical pharmacology and translational research enabling a phase 3 multiregional clinical trial. Clin Transl Sci 2021; 14:1069-1081. [PMID: 33503305 PMCID: PMC8212745 DOI: 10.1111/cts.12972] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 12/08/2020] [Accepted: 12/11/2020] [Indexed: 01/01/2023] Open
Abstract
Abstract The investigational NEDD8‐activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single‐agent azacitidine in patients with higher‐risk myelodysplastic syndrome (higher‐risk MDS), higher‐risk chronic myelomonocytic leukemia (higher‐risk CMML), or low‐blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia‐inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug‐related and disease‐related intrinsic and extrinsic factors. A PubMed literature review (January 2000–November 2019) supported similarity in epidemiology of higher‐risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose‐escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug‐related and disease‐related intrinsic and extrinsic factors supported design of an Asia‐inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia‐inclusive MRCTs.
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