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1
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Wang X, Bajpai AK, Gu Q, Centeno A, Starlard-Davenport A, Prins P, Xu F, Lu L. A systems genetics approach delineates the role of Bcl2 in leukemia pathogenesis. Leuk Res 2022; 114:106804. [PMID: 35182904 PMCID: PMC9272521 DOI: 10.1016/j.leukres.2022.106804] [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: 12/07/2021] [Revised: 01/11/2022] [Accepted: 02/06/2022] [Indexed: 01/11/2023]
Abstract
Leukemia is a group of malignancies of the blood forming tissues, and is characterized by the uncontrolled proliferation of blood cells. In the United States, it accounts for approximately 3.5% and 4% of all cancer-related incidences and mortalities, respectively. The current study aimed to explore the role of Bcl2 and associated genes in leukemia pathogenesis using a systems genetics approach. The transcriptome data from BXD Recombinant Inbred (RI) mice was analyzed to identify the expression of Bcl2 in myeloid cells. eQTL mapping was performed to select the potential chromosomal region and subsequently identify the candidate gene modulating the expression of Bcl2. Furthermore, gene enrichment and protein-protein interaction (PPI) analyses of the Bcl2-coexpressed genes were performed to demonstrate the role of Bcl2 in leukemia pathogenesis. The Bcl2-coexpressed genes were found to be enriched in various hematopoietic system related functions, and multiple pathways related to signaling, immune response, and cancer. The PPI network analysis demonstrated direct interaction of hematopoietic function related genes, such as Bag3, Bak1, Bcl2l11, Bmf, Mapk9, Myc, Ppp2r5c, and Ppp3ca with Bcl2. The eQTL mapping identified a 4.5 Mb genomic region on chromosome 11, potentially regulating the expression of Bcl2. A multi-criteria filtering process identified Top2a, among the genes located in the mapped locus, as the best candidate upstream regulator for Bcl2 expression variation. Hence, the current study provides better insights into the role of Bcl2 in leukemia pathogenesis and demonstrates the significance of our approach in gaining new knowledge on leukemia. Furthermore, our findings from the PPI network analysis and eQTL mapping provide supporting evidence of leukemia-associated genes, which can be further explored for their functional importance in leukemia. DATA AVAILABILITY: The myeloid cell transcriptomic data of the BXD mice used in this study can be accessed through our GeneNetwork (http://www.genenetwork.org) with the accession number of GN144.
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Affiliation(s)
- Xinfeng Wang
- Department of Hematology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Akhilesh Kumar Bajpai
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Qingqing Gu
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA,Department of Cardiology, Affiliated Hospital of Nantong University, Jiangsu 226001, China
| | - Arthur Centeno
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Athena Starlard-Davenport
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Pjotr Prins
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Fuyi Xu
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; School of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, China.
| | - Lu Lu
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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2
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Morales-Martínez M, Vega MI. Roles and Regulation of BCL-xL in Hematological Malignancies. Int J Mol Sci 2022; 23:2193. [PMID: 35216310 PMCID: PMC8876520 DOI: 10.3390/ijms23042193] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/10/2022] [Accepted: 02/11/2022] [Indexed: 12/20/2022] Open
Abstract
Members of the Bcl-2 family are proteins that play an essential role in the regulation of apoptosis, a crucial process in development and normal physiology in multicellular organisms. The essential mechanism of this family of proteins is given by the role of pro-survival proteins, which inhibit apoptosis by their direct binding with their counterpart, the effector proteins of apoptosis. This family of proteins was named after the typical member Bcl-2, which was named for its discovery and abnormal expression in B-cell lymphomas. Subsequently, the structure of one of its members BCL-xL was described, which allowed one to understand much of the molecular mechanism of this family. Due to its role of BCL-xL in the regulation of cell survival and proliferation, it has been of great interest in its study. Due to this, it is important to research its role regarding the development and progression of human malignancies, especially in hematologic malignancies. Due to its variation in expression in cancer, it has been suggested that BCL-xL can or cannot play a role in cancer depending on the cellular or tissue context. This review discusses recent advances in its transcriptional regulation of BCL-xL, as well as the advances regarding the activities of BCL-xL in hematological malignancies, its possible role as a biomarker, and its possible clinical relevance in these malignancies.
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Affiliation(s)
- Mario Morales-Martínez
- Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, México City 06720, Mexico;
| | - Mario I. Vega
- Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, México City 06720, Mexico;
- Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, CA 90073, USA
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3
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Tumor suppressor function of Gata2 in Acute Promyelocytic Leukemia. Blood 2021; 138:1148-1161. [PMID: 34125173 DOI: 10.1182/blood.2021011758] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/06/2021] [Indexed: 11/20/2022] Open
Abstract
Most patients with acute promyelocytic leukemia (APL) can be cured with combined All Trans Retinoic Acid (ATRA) and Arsenic Trioxide therapy, which induce the destruction of PML-RARA, the initiating fusion protein for this disease1. However, the underlying mechanisms by which PML-RARA initiates and maintains APL cells are still not clear. We therefore identified genes that are dysregulated by PML-RARA in mouse and human APL cells, and prioritized GATA2 for functional studies because 1) it is highly expressed in pre-leukemic cells expressing PML-RARA, 2) its high expression persists in transformed APL cells, and 3) spontaneous somatic mutations of GATA2 occur during APL progression in both mice and humans. These and other findings suggested that GATA2 may be upregulated to thwart the proliferative signal generated by PML-RARA, and that its inactivation by mutation (and/or epigenetic silencing) may accelerate disease progression in APL and other forms of AML. Indeed, biallelic knockout of Gata2 with CRISPR/Cas9-mediated gene editing increased the serial replating efficiency of PML-RARA-expressing myeloid progenitors (and also progenitors expressing RUNX1-RUNX1T1, or deficient for Cebpa), increased mouse APL penetrance, and decreased latency. Restoration of Gata2 expression suppressed PML-RARA-driven aberrant self-renewal and leukemogenesis. Conversely, addback of a mutant GATA2R362G protein associated with APL and AML minimally suppressed PML-RARA-induced aberrant self-renewal, suggesting that it is a loss-of-function mutation. These studies reveal a potential role for Gata2 as a tumor suppressor in AML, and suggest that restoration of its function (when inactivated) may provide benefit for AML patients.
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4
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Oncogenic role of lncRNA CRNDE in acute promyelocytic leukemia and NPM1-mutant acute myeloid leukemia. Cell Death Discov 2020; 6:121. [PMID: 33298855 PMCID: PMC7658230 DOI: 10.1038/s41420-020-00359-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/13/2020] [Indexed: 12/22/2022] Open
Abstract
The PML/RARα fusion protein acts in concert with cooperative genetic events in the development of acute promyelocytic leukemia (APL). However, oncogenic long non-coding RNAs (lncRNAs) cooperating with PML/RARα remain under-explored. Here, we first identified a set of pathogenesis-related lncRNAs, aberrantly expressed in APL using RNA-seq data from a large cohort of acute myeloid leukemia (AML) patients and normal counterparts. Among the pathogenesis-related lncRNAs, one of the evolutionarily conservative lncRNAs CRNDE (Colorectal Neoplasia Differentially Expressed) drew our attention. We found that CRNDE was highly expressed in the disease state but not in the preleukemic stage of APL, suggesting that CRNDE might be a secondary event coordinating with PML/RARα to promote APL development. Functional analysis showed that CRNDE knockdown induced differentiation and inhibited proliferation of APL cells, and prolonged survival of APL mice. Further mechanistic studies showed that CRNDE elicited its oncogenic effects through binding the miR-181 family and thereby regulating NOTCH2. Finally, we found that high CRNDE expression was also significantly correlated with NPM1 mutations and contributed to the differentiation block in NPM1-mutant AML. Collectively, our findings shed light on the importance of oncogenic lncRNAs in the development of AML and provide a promising target for AML therapy.
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5
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NLS-RARα contributes to differentiation block and increased leukemogenic potential in vivo. Cell Signal 2019; 65:109431. [PMID: 31654721 DOI: 10.1016/j.cellsig.2019.109431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 12/16/2022]
Abstract
The fusion oncogene, promyelocytic leukemia (PML)-retinoic acid receptor-α (RARα), is crucial for acute promyelocytic leukemia (APL) pathogenesis. Previous studies have reported that PML-RARα is cleaved by neutrophil elastase (NE), an early myeloid-specific serine protease, leading to translocation of the nuclear localization signal (NLS) of the PML protein to the N-terminal of RARα. This study was designed to evaluate the value of NLS-RARα in the early diagnosis of APL. To investigate the potential functional role of NLS-RARα in leukemogenesis, HL-60 and U937 cell lines were transfected with NLS-RARα lentivirus and negative control (LVNC). The results showed that the induced expression of NLS-RARα down-regulated expressions of CD11b, CD11c, and CD14 compared to the LVNC group induced by 1α, 25-dihydroxyvitamin D3(1,25(OH)2D3). This suggested that NLS-RARα overexpression inhibited granulocytic and monocytic differentiation of myeloid leukemia cells. In addition, Wright-Giemsa staining, flow cytometry, respiratory burst assay, and NBT reduction assay all confirmed the importance of NLS-RARα in differentiation. The mechanistic investigations revealed that induced NLS-RARα expression inhibited 1,25(OH)2D3-induced granulocytic differentiation by regulating the cell cycle regulators p19INK4D, p21WAF1/CIP1, cyclinD1, cyclin E1, and pRB. Furthermore, the cleaved protein NLS-RARα enhanced the oncogenicity of U937 cells in NOD/SCID mice. These findings collectively demonstrated that NLS-RARα blocked granulocytic and monocytic differentiation of myeloid leukemia cells by inhibiting the downstream targets of the RARα signal pathway and the cell cycle. This may provide a promising new target and method for diagnosing and treating APL.
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6
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Abstract
I started research in high school, experimenting on immunological tolerance to transplantation antigens. This led to studies of the thymus as the site of maturation of T cells, which led to the discovery, isolation, and clinical transplantation of purified hematopoietic stem cells (HSCs). The induction of immune tolerance with HSCs has led to isolation of other tissue-specific stem cells for regenerative medicine. Our studies of circulating competing germline stem cells in colonial protochordates led us to document competing HSCs. In human acute myelogenous leukemia we showed that all preleukemic mutations occur in HSCs, and determined their order; the final mutations occur in a multipotent progenitor derived from the preleukemic HSC clone. With these, we discovered that CD47 is an upregulated gene in all human cancers and is a "don't eat me" signal; blocking it with antibodies leads to cancer cell phagocytosis. CD47 is the first known gene common to all cancers and is a target for cancer immunotherapy.
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Affiliation(s)
- Irving Weissman
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, and Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, Stanford, CA 94305
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7
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Li Q, Wu Y, Zhang Y, Sun H, Lu Z, Du K, Fang S, Li W. miR-125b regulates cell progression in chronic myeloid leukemia via targeting BAK1. Am J Transl Res 2016; 8:447-459. [PMID: 27158338 PMCID: PMC4846895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 12/29/2015] [Indexed: 06/05/2023]
Abstract
Chronic myeloid leukemia (CML) is a type of malignant tumor characterized by the accumulation of a large number of immature white blood cells in the blood and bone marrow. BAK1 was predicted to be the target gene of microRNA-451 (miR-125b). The present study was designed to illustrate the mechanism of miR-125b in regulating CML via targeting BAK1. In this study, we found that the expression of miR-125b increased strongly, whereas the expression of BAK1 decreased significantly in CML patients and CML cell lines compared with healthy controls. Moreover, the luciferase report assay confirmed the interaction between miR-125b and BAK1 mRNA. After transfection of the miR-125b mimic or miR-125b inhibitor into CML cells, we found that the inhibition of miR-125b decreased the proliferation rates and promoted apoptosis with cell cycle arrest at the G0/G1 phase in both K562 and NB-4 cells, increased the expression of BAK1 and Caspase-3, and decreased the expression of Bcl-2 and c-myc; the miR-125b mimic yielded the opposite results. In addition, siBAK1 offset the suppression effect of the miR-125b inhibitor in K562 cells, indicating that miR-125b promotes these cellular processes by inhibiting the expression of BAK1. Further in vivo experiments supported these findings because miR-125b suppression reduced CML growth in mice. Taken together, our study suggests that the down-regulation of miR-125b affects the expression of BAK1, promotes cell apoptosis and inhibits cell proliferation, leading to up-regulated expression of pro-apoptosis factors, down-regulated expression of anti-apoptosis factors in the mitochondrial apoptotic pathway, and decreased tumor size and weight of CML in vivo. These results provide a potential therapeutic strategy for CML.
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Affiliation(s)
- Quan Li
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and ScienceJinzhou Road 136, Xiangyang 441053, China
| | - Yaohui Wu
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology1277 Jiefang Avenue, Wuhan 430022, China
| | - Yongkang Zhang
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and ScienceJinzhou Road 136, Xiangyang 441053, China
| | - Huapeng Sun
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and ScienceJinzhou Road 136, Xiangyang 441053, China
| | - Zhaoli Lu
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and ScienceJinzhou Road 136, Xiangyang 441053, China
| | - Ke Du
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and ScienceJinzhou Road 136, Xiangyang 441053, China
| | - Shanshan Fang
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and ScienceJinzhou Road 136, Xiangyang 441053, China
| | - Weiming Li
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology1277 Jiefang Avenue, Wuhan 430022, China
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8
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Wree A, Johnson CD, Font-Burgada J, Eguchi A, Povero D, Karin M, Feldstein AE. Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation. Cell Death Differ 2015; 22:1985-94. [PMID: 25909884 PMCID: PMC4816107 DOI: 10.1038/cdd.2015.46] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 03/17/2015] [Indexed: 02/07/2023] Open
Abstract
Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion--a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid(Δhep)) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid(Δhep) mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid(Δhep) animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF-α, IL-1ß, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid(Δhep) mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid(Δhep) mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid(Δhep) and Bid(flo/flo) mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival.
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Affiliation(s)
- A Wree
- Department of Pediatrics, University of California—San Diego, La Jolla, CA, USA
| | - C D Johnson
- Department of Pediatrics, University of California—San Diego, La Jolla, CA, USA
| | - J Font-Burgada
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California—San Diego, La Jolla, CA, USA
| | - A Eguchi
- Department of Pediatrics, University of California—San Diego, La Jolla, CA, USA
| | - D Povero
- Department of Pediatrics, University of California—San Diego, La Jolla, CA, USA
| | - M Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California—San Diego, La Jolla, CA, USA
| | - A E Feldstein
- Department of Pediatrics, University of California—San Diego, La Jolla, CA, USA
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9
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Gaillard C, Tokuyasu TA, Rosen G, Sotzen J, Vitaliano-Prunier A, Roy R, Passegué E, de Thé H, Figueroa ME, Kogan SC. Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation. Haematologica 2015; 100:1064-75. [PMID: 26088929 DOI: 10.3324/haematol.2014.123018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 05/06/2015] [Indexed: 12/15/2022] Open
Abstract
Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality implicated in this pathology, but the mechanisms by which this chimeric fusion protein initiates disease are incompletely understood. Identifying PML/RARA targets in vivo is critical for comprehending the road to pathogenesis. Utilizing a novel sorting strategy, we isolated highly purified promyelocyte populations from normal and young preleukemic animals, carried out microarray and methylation profiling analyses, and compared the results from the two groups of animals. Surprisingly, in the absence of secondary lesions, PML/RARA had an overall limited impact on both the transcriptome and methylome. Of interest, we did identify down-regulation of secondary and tertiary granule genes as the first step engaging the myeloid maturation block. Although initially not sufficient to arrest terminal granulopoiesis in vivo, such alterations set the stage for the later, complete differentiation block seen in leukemia. Further, gene set enrichment analysis revealed that PML/RARA promyelocytes exhibit a subtle increase in expression of cell cycle genes, and we show that this leads to both increased proliferation of these cells and expansion of the promyelocyte compartment. Importantly, this proliferation signature was absent from the poorly leukemogenic p50/RARA fusion model, implying a critical role for PML in the altered cell-cycle kinetics and ability to initiate leukemia. Thus, our findings challenge the predominant model in the field and we propose that PML/RARA initiates leukemia by subtly shifting cell fate decisions within the promyelocyte compartment.
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Affiliation(s)
- Coline Gaillard
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA Institut Universitaire d'Hématologie, Université Paris-Diderot UMR 944/7212, France
| | - Taku A Tokuyasu
- Computational Biology Core, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Galit Rosen
- Center for Cancer and Blood Disorders, Phoenix Children's Hospital, AZ, USA
| | - Jason Sotzen
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | | | - Ritu Roy
- Computational Biology Core, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Emmanuelle Passegué
- Department of Medicine, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA
| | - Hugues de Thé
- Institut Universitaire d'Hématologie, Université Paris-Diderot UMR 944/7212, France
| | - Maria E Figueroa
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Scott C Kogan
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
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10
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Perri M, Yap JL, Yu J, Cione E, Fletcher S, Kane MA. BCL-xL/MCL-1 inhibition and RARγ antagonism work cooperatively in human HL60 leukemia cells. Exp Cell Res 2014; 327:183-91. [PMID: 25088254 PMCID: PMC4727751 DOI: 10.1016/j.yexcr.2014.07.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 07/18/2014] [Accepted: 07/22/2014] [Indexed: 12/25/2022]
Abstract
The acute promyelocytic leukemia (APL) subtype of acute myeloid leukemia (AML) is characterized by chromosomal translocations that result in fusion proteins, including the promyelocytic leukemia-retinoic acid receptor, alpha fusion protein (PML-RARα). All-trans retinoic acid (atRA) treatment is the standard drug treatment for APL yielding cure rates > 80% by activating transcription and proteasomal degradation of retinoic acid receptor, alpha (RARα). Whereas combination therapy with As2O3 has increased survival further, patients that experience relapse and are refractory to atRA and/or As2O3 is a clinically significant problem. BCL-2 family proteins regulate apoptosis and over-expression of anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) family proteins has been associated with chemotherapeutic resistance in APL including impairment of the ability of atRA to induce growth arrest and differentiation. Here we investigated the novel BH3 domain mimetic, JY-1-106, which antagonizes the anti-apoptotic BCL-2 family members B-cell lymphoma-extra large (BCL-xL) and myeloid cell leukemia-1 (MCL-1) alone and in combination with retinoids including atRA, AM580 (RARα agonist), and SR11253 (RARγ antagonist). JY-1-106 reduced cell viability in HL-60 cells alone and in combination with retinoids. The combination of JY-1-106 and SR11253 had the greatest impact on cell viability by stimulating apoptosis. These studies indicate that dual BCL-xL/MCL-1 inhibitors and retinoids could work cooperatively in leukemia treatment.
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MESH Headings
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Apoptosis/drug effects
- Benzamides/administration & dosage
- Benzoates/administration & dosage
- Blotting, Western
- Cell Proliferation/drug effects
- Humans
- Leukemia, Promyelocytic, Acute/drug therapy
- Leukemia, Promyelocytic, Acute/metabolism
- Leukemia, Promyelocytic, Acute/pathology
- Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Receptors, Retinoic Acid/agonists
- Receptors, Retinoic Acid/antagonists & inhibitors
- Retinoic Acid Receptor alpha
- Reverse Transcriptase Polymerase Chain Reaction
- Tetrahydronaphthalenes/administration & dosage
- Tretinoin/administration & dosage
- Tumor Cells, Cultured
- bcl-X Protein/antagonists & inhibitors
- para-Aminobenzoates/administration & dosage
- Retinoic Acid Receptor gamma
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Affiliation(s)
- Mariarita Perri
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA
| | - Jeremy L Yap
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA
| | - Jianshi Yu
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA
| | - Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences, Ed. Polifunzionale, University of Calabria, 87036 Rende, CS, Italy
| | - Steven Fletcher
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA
| | - Maureen A Kane
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA.
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11
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Lo-Coco F, Hasan SK. Understanding the molecular pathogenesis of acute promyelocytic leukemia. Best Pract Res Clin Haematol 2014; 27:3-9. [DOI: 10.1016/j.beha.2014.04.006] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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12
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Zhou GB, Chen SJ, Chen Z. Acute promyelocytic leukemia: A model of molecular target based therapy. Hematology 2013; 10 Suppl 1:270-80. [PMID: 16188687 DOI: 10.1080/10245330512331390519] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Leukemia, a group of hematological malignancies characterized by clonal expansion of hematopoietic cells with uncontrolled proliferation, decreased apoptosis and blocked differentiation, is one of the most notorious enemies of mankind which accounts for some 300,000 new cases and 222,000 deaths each year worldwide. Leukemia can be divided into acute or chronic, lymphoid or myeloid types, based on the disease progression and hematopoietic lineages involved 5. The responses of leukemia to therapies differ from one type or subtype to another. Hence, to improve the clinical outcome, the therapeutic strategies should be disease pathogenesis-based and individualized. The close collaboration between bench and bedside may not only shed new lights on leukemogenesis, gain insights into therapeutic mechanisms, but also provide opportunities for designing more rational therapies. The development of curative approaches for acute promyelocytic leukemia (APL) may serve as a paradigm.
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Affiliation(s)
- Guang-Biao Zhou
- Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Second Medical University 197, Rui Jin Road II, Shanghai, 200025, China
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13
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Machida K. Tumor-initiating stem-like cells and drug resistance: carcinogenesis through Toll-like receptors, environmental factors, and virus. Drug Deliv Transl Res 2013; 3:152-64. [PMID: 25787983 PMCID: PMC10578060 DOI: 10.1007/s13346-012-0115-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Neoplasms contain distinct subpopulations of cells known as tumor-initiating stem-like cells (TICs) that have been identified as key drivers of tumor growth and malignant progression with drug resistance. Stem cells normally proliferate through self-renewing divisions in which the two daughter cells differ markedly in their proliferative potential, with one displaying the differentiation phenotypes and another retaining self-renewing activity. Therefore, understanding the molecular mechanisms of hepatocarcinogenesis will be required for the eventual development of improved therapeutic modalities for treating hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) and hepatitis B virus is a major cause of HCC. Compelling epidemiologic evidence identifies obesity and alcohol as co-morbidity factors that can increase the risk of HCV patients for HCC, especially in alcoholics or obese patients. The mechanisms underlying liver oncogenesis, and how environmental factors contribute to this process, are not yet understood. The HCV-Toll-like receptor 4 (TLR4)-Nanog signaling network is established since alcohol/obesity-associated endotoxemia then activates TLR4 signaling, resulting in the induction of the stem cell marker Nanog expression and liver tumors. Liver TICs are highly sensitized to leptin and exposure of TICs to leptin increases the expression and activity of an intrinsic pluripotency-associated transcriptional network comprised of signal transducer and activator of transcription 3, SOX2, OCT4, and Nanog. Stimulation of the pluripotency network may have significant implications for hepatocellular oncogenesis via genesis and maintenance of TICs. It is important to understand how HCV induces liver cancer through genesis of TICs so that better prevention and treatment can be found. This article reviews the oncogenic pathways to generate TICs.
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Affiliation(s)
- Keigo Machida
- Department of Molecular Microbiology and Immunology, Research Center for ALPD and Cirrhosis, University of Southern California School of Medicine, 503C-HMR, Los Angeles, CA, 90033, USA,
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Abstract
Acute promyelocytic leukemia (APL) is initiated by the PML-RARA (PR) fusion oncogene and has a characteristic expression profile that includes high levels of the Notch ligand Jagged-1 (JAG1). In this study, we used a series of bioinformatic, in vitro, and in vivo assays to assess the role of Notch signaling in human APL samples, and in a PML-RARA knock-in mouse model of APL (Ctsg-PML-RARA). We identified a Notch expression signature in both human primary APL cells and in Kit+Lin-Sca1+ cells from pre-leukemic Ctsg-PML-RARA mice. Both genetic and pharmacologic inhibition of Notch signaling abrogated the enhanced self-renewal seen in hematopoietic stem/progenitor cells from pre-leukemic Ctsg-PML-RARA mice, but had no influence on cells from age-matched wild-type mice. In addition, six of nine murine APL tumors tested displayed diminished growth in vitro when Notch signaling was inhibited pharmacologically. Finally, we found that genetic inhibition of Notch signaling with a dominant-negative Mastermind-like protein reduced APL growth in vivo in a subset of tumors. These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis.
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15
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Abstract
Human RAD9 is a key cell-cycle checkpoint protein that participates in DNA repair, activation of multiple cell cycle phase checkpoints, and apoptosis. Aberrant RAD9 expression has been linked to breast, lung, thyroid, skin, and prostate tumorigenesis. Overexpression of RAD9 interacts with BCL-2 proteins and blocks the binding sites of BCL-2 family proteins to interact with chemotherapeutic drugs and leads to drug resistance. Focusing on this interaction, the present study was designed to identify the interaction sites of RAD9 to bind BCL-2 protein and also to inhibit RAD9-BCL-2 interactions by designing novel small molecule inhibitors using pharmacophore modeling and to restore BCL-2 for interacting with anticancer drugs. The bioactive molecules of natural origin act as excellent leads for new drug development. Thus, in the present study, we used the compounds of natural origin like camptothecin, ascididemin, and Dolastatin and also compared them with synthetic molecule NSC15520. The results revealed that camptothecin can act as an effective inhibitor among all the ligands taken and can be used as an RAD9 inhibitor. The amino acids ARG45 and ALA134 of RAD9 protein are interacting commonly with the drugs and BCL-2 protein.
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16
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Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome. Blood 2012; 120:2475-83. [PMID: 22855610 DOI: 10.1182/blood-2012-05-430736] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Programmed cell death or apoptosis is a prominent feature of low-risk myelodysplastic syndromes (MDS), although the underlying mechanism remains controversial. High-risk MDS have less apoptosis associated with increased expression of the prosurvival BCL2-related proteins. To address the mechanism and pathogenic role of apoptosis and BCL2 expression in MDS, we used a mouse model resembling human MDS, in which the fusion protein NUP98-HOXD13 (NHD13) of the chromosomal translocation t(2;11)(q31;p15) is expressed in hematopoietic cells. Hematopoietic stem and progenitor cells from 3-month-old mice had increased rates of apoptosis associated with increased cell cycling and DNA damage. Gene expression profiling of these MDS progenitors revealed a specific reduction in Bcl2. Restoration of Bcl2 expression by a BCL2 transgene blocked apoptosis of the MDS progenitors, which corrected the macrocytic anemia. Blocking apoptosis also restored cell-cycle quiescence and reduced DNA damage in the MDS progenitors. We expected that preventing apoptosis would accelerate malignant transformation to acute myeloid leukemia (AML). However, contrary to expectations, preventing apoptosis of premalignant cells abrogated transformation to AML. In contrast to the current dogma that overcoming apoptosis is an important step toward cancer, this work demonstrates that gaining a survival advantage of premalignant cells may delay or prevent leukemic progression.
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Zhu X, Zhang H, Qian M, Zhao X, Yang W, Wang P, Zhang J, Wang K. The significance of low PU.1 expression in patients with acute promyelocytic leukemia. J Hematol Oncol 2012; 5:22. [PMID: 22569057 PMCID: PMC3407792 DOI: 10.1186/1756-8722-5-22] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 05/08/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Although the importance of the hematopoietic transcription factor PU.1 in acute myeloid leukemia (AML) has been demonstrated, the expression of PU.1 in acute promyelocytic leukemia (APL) patient samples awaits further investigation. The current study used APL patient samples to assess the expression pattern of PU.1 in the initiation and progression of APL. FINDINGS We used real-time RT-PCR to compare PU.1 expression between de novo APL patient samples and normal blood specimens, and the results indicated that PU.1 expression was significantly lower in newly diagnosed APL patient samples as compared to normal hematopoietic cells. Further evidence showed a significant inverse correlation between the expression level of PML-RARα and that of PU.1. In addition, we analyzed the correlation between PML-RARα and PU.1 expression in a large population of AML patients retrieved from the expression profiles. The results showed that PU.1 expression was lower in patients with APL than other AML subtypes and there was also a trend towards increasing PU.1 expression from AML-M0 to AML-M5, with the exception of AML-M3 (APL). These observations suggested that PU.1 expression was reduced by PML-RARα in APL patients. Furthermore, we measured PU.1 expression in APL-initiating cells isolated from de novo APL patients by side population cell analysis and found that suppression of PU.1 expression occurred concurrently with PML-RARα expression, indicating the pivotal role of PU.1 in APL initiation. CONCLUSION Our findings provide evidence that low PU.1 expression in APL patients is required for disease initiation and progression.
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Affiliation(s)
- Xuehua Zhu
- State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Rui-Jin Hospital, SJTUSM, Shanghai, China
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18
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Wartman LD, Larson DE, Xiang Z, Ding L, Chen K, Lin L, Cahan P, Klco JM, Welch JS, Li C, Payton JE, Uy GL, Varghese N, Ries RE, Hoock M, Koboldt DC, McLellan MD, Schmidt H, Fulton RS, Abbott RM, Cook L, McGrath SD, Fan X, Dukes AF, Vickery T, Kalicki J, Lamprecht TL, Graubert TA, Tomasson MH, Mardis ER, Wilson RK, Ley TJ. Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression. J Clin Invest 2011; 121:1445-55. [PMID: 21436584 DOI: 10.1172/jci45284] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Accepted: 01/19/2011] [Indexed: 01/12/2023] Open
Abstract
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). It is characterized by the t(15;17)(q22;q11.2) chromosomal translocation that creates the promyelocytic leukemia-retinoic acid receptor α (PML-RARA) fusion oncogene. Although this fusion oncogene is known to initiate APL in mice, other cooperating mutations, as yet ill defined, are important for disease pathogenesis. To identify these, we used a mouse model of APL, whereby PML-RARA expressed in myeloid cells leads to a myeloproliferative disease that ultimately evolves into APL. Sequencing of a mouse APL genome revealed 3 somatic, nonsynonymous mutations relevant to APL pathogenesis, of which 1 (Jak1 V657F) was found to be recurrent in other affected mice. This mutation was identical to the JAK1 V658F mutation previously found in human APL and acute lymphoblastic leukemia samples. Further analysis showed that JAK1 V658F cooperated in vivo with PML-RARA, causing a rapidly fatal leukemia in mice. We also discovered a somatic 150-kb deletion involving the lysine (K)-specific demethylase 6A (Kdm6a, also known as Utx) gene, in the mouse APL genome. Similar deletions were observed in 3 out of 14 additional mouse APL samples and 1 out of 150 human AML samples. In conclusion, whole genome sequencing of mouse cancer genomes can provide an unbiased and comprehensive approach for discovering functionally relevant mutations that are also present in human leukemias.
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Affiliation(s)
- Lukas D Wartman
- Department of Internal Medicine, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri, USA
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19
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Uy GL, Lane AA, Welch JS, Grieselhuber NR, Payton JE, Ley TJ. A protease-resistant PML-RAR{alpha} has increased leukemogenic potential in a murine model of acute promyelocytic leukemia. Blood 2010; 116:3604-10. [PMID: 20647568 PMCID: PMC2981479 DOI: 10.1182/blood-2008-11-189282] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2008] [Accepted: 07/12/2010] [Indexed: 11/20/2022] Open
Abstract
Previous studies in our laboratory demonstrated that the azurophil granule protease neutrophil elastase (NE) cleaves promyelocytic leukemia-retinoic acid receptor (PML-RAR)α (PR), the fusion protein that initiates acute promyelocytic leukemia (APL). Further, NE deficiency reduces the penetrance of APL in a murine model of this disease. We therefore predicted that NE-mediated PR cleavage might be important for its ability to initiate APL. To test this hypothesis, we generated a mouse expressing NE-resistant PR. These mice developed APL indistinguishable from wild-type PR, but with significantly reduced latency (median leukemia-free survival of 274 days vs 473 days for wild-type PR, P < .001). Resistance to proteolysis may increase the abundance of full-length PR protein in early myeloid cells, and our previous data suggested that noncleaved PR may be less toxic to early myeloid cells. Together, these effects appear to increase the leukemogenicity of NE-resistant PR, contrary to our previous prediction. We conclude that NE deficiency may reduce APL penetrance via indirect mechanisms that are still NE dependent.
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Affiliation(s)
- Geoffrey L Uy
- Section of Stem Cell Biology, Division of Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA
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20
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Burchiel SW, Mitchell LA, Lauer FT, Sun X, McDonald JD, Hudson LG, Liu KJ. Immunotoxicity and biodistribution analysis of arsenic trioxide in C57Bl/6 mice following a 2-week inhalation exposure. Toxicol Appl Pharmacol 2009; 241:253-9. [PMID: 19800901 PMCID: PMC2843624 DOI: 10.1016/j.taap.2009.09.019] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Revised: 09/22/2009] [Accepted: 09/25/2009] [Indexed: 02/06/2023]
Abstract
In these studies the immunotoxicity of arsenic trioxide (ATO, As(2)O(3)) was evaluated in mice following 14 days of inhalation exposures (nose only, 3 h per day) at concentrations of 50 microg/m(3) and 1 mg/m(3). A biodistribution analysis performed immediately after inhalation exposures revealed highest levels of arsenic in the kidneys, bladder, liver, and lung. Spleen cell levels were comparable to those found in the blood, with the highest concentration of arsenic detected in the spleen being 150 microg/g tissue following the 1 mg/m(3) exposures. No spleen cell cytotoxicity was observed at either of the two exposure levels. There were no changes in spleen cell surface marker expression for B cells, T cells, macrophages, and natural killer (NK) cells. There were also no changes detected in the B cell (LPS-stimulated) and T cell (Con A-stimulated) proliferative responses of spleen cells, and no changes were found in the NK-mediated lysis of Yac-1 target cells. The primary T-dependent antibody response was, however, found to be highly susceptible to ATO suppression. Both the 50 microg/m(3) and 1 mg/m(3) exposures produced greater than 70% suppression of the humoral immune response to sheep red blood cells. Thus, the primary finding of this study is that the T-dependent humoral immune response is extremely sensitive to suppression by ATO and assessment of humoral immune responses should be considered in evaluating the health effects of arsenic containing agents.
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Affiliation(s)
- Scott W Burchiel
- Toxicology and Pharmaceutical Sciences Program, The University of New Mexico College of Pharmacy, Albuquerque, NM 87131, USA.
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21
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FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood 2009; 114:5034-43. [PMID: 19808698 DOI: 10.1182/blood-2008-12-196055] [Citation(s) in RCA: 200] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Myeloid cell leukemia-1 (MCL-1) is an essential survival factor for hematopoiesis. In humans, hematopoietic stem cells (HSCs) express MCL-1 at the highest level in response to FMS-like tyrosine kinase-3 (FLT3) signaling. We here show that this FLT3-dependent stem cell maintenance system also plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34(+)CD38(-) LSC fraction expresses high levels of FLT3 as well as MCL-1, even compared with normal HSCs. Treatment with FLT3 ligand induced further MCL-1 up-regulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing the highest levels of MCL-1 constituted AML with FLT3-internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Finally, transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its signal transducer and activator of transcription 5 (STAT5)-docking domains. This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by up-regulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling.
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22
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Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia. Blood 2009; 114:5415-25. [PMID: 19797526 DOI: 10.1182/blood-2008-10-182071] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Acute promyelocytic leukemia (APL) is characterized by a block in differentiation and accumulation of promyelocytes in the bone marrow and blood. The majority of APL patients harbor the t(15:17) translocation leading to expression of the fusion protein promyelocytic-retinoic acid receptor alpha. Treatment with retinoic acid leads to degradation of promyelocytic-retinoic acid receptor alpha protein and disappearance of leukemic cells; however, 30% of APL patients relapse after treatment. One potential mechanism for relapse is the persistence of cancer "stem" cells in hematopoietic organs after treatment. Using a novel sorting strategy we developed to isolate murine myeloid cells at distinct stages of differentiation, we identified a population of committed myeloid cells (CD34(+), c-kit(+), FcgammaRIII/II(+), Gr1(int)) that accumulates in the spleen and bone marrow in a murine model of APL. We observed that these cells are capable of efficiently generating leukemia in recipient mice, demonstrating that this population represents the APL cancer-initiating cell. These cells down-regulate the transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) possibly through a methylation-dependent mechanism, indicating that C/EBPalpha deregulation contributes to transformation of APL cancer-initiating cells. Our findings provide further understanding of the biology of APL by demonstrating that a committed transformed progenitor can initiate and propagate the disease.
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23
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Kang YH, Lee SJ. The role of p38 MAPK and JNK in Arsenic trioxide-induced mitochondrial cell death in human cervical cancer cells. J Cell Physiol 2008; 217:23-33. [DOI: 10.1002/jcp.21470] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice. Blood 2008; 112:1434-42. [PMID: 18552208 DOI: 10.1182/blood-2008-01-132084] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Therapy-related acute myelogenous leukemia (t-AML) is an important late adverse effect of alkylator chemotherapy. Susceptibility to t-AML has a genetic component, yet specific genetic variants that influence susceptibility are poorly understood. We analyzed an F(2) intercross (n = 282 mice) between mouse strains resistant or susceptible to t-AML induced by the alkylator ethyl-N-nitrosourea (ENU) to identify genes that regulate t-AML susceptibility. Each mouse carried the hCG-PML/RARA transgene, a well-characterized initiator of myeloid leukemia. In the absence of ENU treatment, transgenic F(2) mice developed leukemia with higher incidence (79.4% vs 12.5%) and at earlier time points (108 days vs 234 days) than mice in the resistant background. ENU treatment of F(2) mice further increased incidence (90.4%) and shortened median survival (171 vs 254 days). We genotyped F(2) mice at 384 informative single nucleotide polymorphisms across the genome and performed quantitative trait locus (QTL) analysis. Thirteen QTLs significantly associated with leukemia-free survival, spleen weight, or white blood cell count were identified on 8 chromosomes. These results suggest that susceptibility to ENU-induced leukemia in mice is a complex trait governed by genes at multiple loci. Improved understanding of genetic risk factors should lead to tailored treatment regimens that reduce risk for patients predisposed to t-AML.
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25
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Evidence of functional interaction between NuMA-RARα and RXRα in an in vivo model of acute promyelocytic leukemia. Oncogene 2008; 27:4666-77. [DOI: 10.1038/onc.2008.106] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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26
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McCormack E, Bruserud O, Gjertsen BT. Review: genetic models of acute myeloid leukaemia. Oncogene 2008; 27:3765-79. [PMID: 18264136 DOI: 10.1038/onc.2008.16] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The use of genetically engineered mice (GEM) have been critical in understanding disease states such as cancer, and none more so than acute myelogenous leukaemia (AML), a disease characterized by over 100 distinct chromosomal translocations. A substantial proportion of cases exhibiting recurrent reciprocal translocations at diagnosis, such as t(8;21) or t(15;17) have been exhaustively studied and are currently employed in clinical diagnosis. However, a definitive conclusion regarding the leukaemogenic potential of defined transgenes for this disease remains elusive. While it is increasingly apparent that a number of cooperating mutations are necessary to develop a leukaemic phenotype, the number of models reflecting these synergisms remains few. Furthermore, little emphasis has been paid to the effect of chromosomal translocations other than recurrent genetic abnormalities, with no models reflecting the multiple abnormalities observed in high-risk cases of AML accounting for 8-10% of adult AML. Here we review the differing technologies employed in generation of GEM of AML. We discuss the relevance of GEM AML from embryonic stem cell-mediated (for example retinoic acid receptor-alpha fusions and AML1/ETO) models; through to the valuable retroviral-mediated gene transfer models. The latter have been used to great effect in defining the transforming properties of chromosomal translocation products such as MLL (found in 5-6% of all AML cases) and NUP98 (denoting poor prognosis in therapy-related disease) and particularly when co-transduced with bad prognostic factors such as Flt3 mutations. Finally, we comment on the emergence of newer transduction technologies, which can regulate the level of expression to defined cell lineages in both primary murine and human xenografts, and discuss how combining multiple genetic modalities, more relevant models of this complex disease are being generated.
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Affiliation(s)
- E McCormack
- Institute of Medicine, Haematology Section, University of Bergen, Bergen, Norway
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27
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Omidvar N, Kogan S, Beurlet S, le Pogam C, Janin A, West R, Noguera ME, Reboul M, Soulie A, Leboeuf C, Setterblad N, Felsher D, Lagasse E, Mohamedali A, Thomas NSB, Fenaux P, Fontenay M, Pla M, Mufti GJ, Weissman I, Chomienne C, Padua RA. BCL-2 and mutant NRAS interact physically and functionally in a mouse model of progressive myelodysplasia. Cancer Res 2008; 67:11657-67. [PMID: 18089795 DOI: 10.1158/0008-5472.can-07-0196] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Myelodysplastic syndromes (MDS) are clonal stem cell hematologic disorders that evolve to acute myeloid leukemia (AML) and thus model multistep leukemogenesis. Activating RAS mutations and overexpression of BCL-2 are prognostic features of MDS/AML transformation. Using NRASD12 and BCL-2, we created two distinct models of MDS and AML, where human (h)BCL-2 is conditionally or constitutively expressed. Our novel transplantable in vivo models show that expression of hBCL-2 in a primitive compartment by mouse mammary tumor virus-long terminal repeat results in a disease resembling human MDS, whereas the myeloid MRP8 promoter induces a disease with characteristics of human AML. Expanded leukemic stem cell (Lin(-)/Sca-1(+)/c-Kit(+)) populations and hBCL-2 in the increased RAS-GTP complex within the expanded Sca-1(+) compartment are described in both MDS/AML-like diseases. Furthermore, the oncogenic compartmentalizations provide the proapoptotic versus antiapoptotic mechanisms, by activating extracellular signal-regulated kinase and AKT signaling, in determination of the neoplastic phenotype. When hBCL-2 is switched off with doxycycline in the MDS mice, partial reversal of the phenotype was observed with persistence of bone marrow blasts and tissue infiltration as RAS recruits endogenous mouse (m)BCL-2 to remain active, thus demonstrating the role of the complex in the disease. This represents the first in vivo progression model of MDS/AML dependent on the formation of a BCL-2:RAS-GTP complex. The colocalization of BCL-2 and RAS in the bone marrow of MDS/AML patients offers targeting either oncogene as a therapeutic strategy.
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Affiliation(s)
- Nader Omidvar
- Institut National de la Sante et de la Recherche Medicale U718 and 728, Université Paris 7 Denis Diderot, Faculté de Médicine, Institut Universitaire d'Hématologie-IFR105, Paris, France
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28
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Rassool FV, Gaymes TJ, Omidvar N, Brady N, Beurlet S, Pla M, Reboul M, Lea N, Chomienne C, Thomas NSB, Mufti GJ, Padua RA. Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia? Cancer Res 2007; 67:8762-71. [PMID: 17875717 DOI: 10.1158/0008-5472.can-06-4807] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop acute myelogenous leukemia (AML). The molecular basis for MDS progression is unknown, but a key element in MDS disease progression is loss of chromosomal material (genomic instability). Using our two-step mouse model for myeloid leukemic disease progression involving overexpression of human mutant NRAS and BCL2 genes, we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error-prone repair of double-strand breaks (DSB) by nonhomologous end-joining. There is a concomitant increase in reactive oxygen species (ROS) in these transgenic mice with disease progression. Importantly, RAC1, an essential component of the ROS-producing NADPH oxidase, is downstream of RAS, and we show that ROS production in NRAS/BCL2 mice is in part dependent on RAC1 activity. DNA damage and error-prone repair can be decreased or reversed in vivo by N-acetyl cysteine antioxidant treatment. Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with MDS disease progression. These data suggest treatment strategies that target RAS/RAC pathways and ROS production in human MDS/AML.
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Affiliation(s)
- Feyruz V Rassool
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201-1509, USA.
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Abstract
To elucidate the molecular mechanisms underlying normal and malignant hematopoietic development, it is critical to identify developmental intermediates for each lineage downstream of hematopoietic stem cells. Recent advances in prospective isolation of hematopoietic stem and progenitor cells, and efficient xenogeneic transplantation systems have provided a detailed developmental map in both mouse and human hematopoiesis, demonstrating that surface phenotypes of mouse stem-progenitor cells and their human counterparts are considerably different. Here, we summarize the phenotype and functional properties and their differences of hematopoietic stem and progenitor cell populations between mouse and human.
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30
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Zhou GB, Zhang J, Wang ZY, Chen SJ, Chen Z. Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy. Philos Trans R Soc Lond B Biol Sci 2007; 362:959-71. [PMID: 17317642 PMCID: PMC2435563 DOI: 10.1098/rstb.2007.2026] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
To turn a disease from highly fatal to highly curable is extremely difficult, especially when the disease is a type of cancer. However, we can gain some insight into how this can be done by looking back over the 50-year history of taming acute promyelocytic leukaemia (APL). APL is the M3 type of acute myeloid leukaemia characterized by an accumulation of abnormal promyelocytes in bone marrow, a severe bleeding tendency and the presence of the chromosomal translocation t(15;17) or variants. APL was considered the most fatal type of acute leukaemia five decades ago and the treatment of APL was a nightmare for physicians. Great efforts have been made by scientists worldwide to conquer this disease. The first use of chemotherapy (CT) was unsuccessful due to lack of supportive care and cytotoxic-agent-related exacerbated coagulopathy. The first breakthrough came from the use of anthracyclines which improved the complete remission (CR) rate, though the 5-year overall survival could only be attained in a small proportion of patients. A rational and intriguing hypothesis, to induce differentiation of APL cells rather than killing them, was raised in the 1970s. Laudably, the use of all-trans retinoic acid (ATRA) in treating APL resulted in terminal differentiation of APL cells and a 90-95% CR rate of patients, turning differentiation therapy in cancer treatment from hypothesis to practice. The combination of ATRA with CT further improved the 5-year overall survival. When arsenic trioxide (ATO) was used to treat relapsed APL not only the patients but also the ancient drug were revived. ATO exerts dose-dependent dual effects on APL cells: at low concentration, ATO induces partial differentiation, while at relatively high concentration, it triggers apoptosis. Of note, both ATRA and ATO trigger catabolism of the PML-RARalpha fusion protein which is the key player in APL leukaemogenesis generated from t(15;17), targeting the RARalpha (retinoic acid receptor alpha) or promyelocytic leukaemia (PML) moieties, respectively. Hence, in treating APL both ATRA and ATO represent paradigms for molecularly targeted therapy. At molecular level, ATRA and ATO synergistically modulate multiple downstream pathways/cascades. Strikingly, a clearance of PML-RARalpha transcript in an earlier and more thorough manner, and a higher quality remission and survival in newly diagnosed APL are achieved when ATRA is combined with ATO, as compared to either monotherapy, making APL a curable disease. Thus, the story of APL can serve as a model for the development of curative approaches for disease; it suggests that molecularly synergistic targeted therapies are powerful tools in cancer, and dissection of disease pathogenesis or anatomy of the cancer genome is critical in developing molecular target-based therapies.
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Affiliation(s)
- Guang-Biao Zhou
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine (SJTUSM)197, Ruijin Road II, Shanghai 200025, People's Republic of China
- Guangzhou Institute of Biomedicine and Health, Chinese Academy of SciencesGuangzhou Sciences Park, Guangzhou 510663, People's Republic of China
| | - Ji Zhang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine (SJTUSM)197, Ruijin Road II, Shanghai 200025, People's Republic of China
- Institute of Health Science, SJTUSM and Shanghai Institutes of Biological Sciences, CASSouth Chongqing Road, Shanghai 200025, People's Republic of China
| | - Zhen-Yi Wang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine (SJTUSM)197, Ruijin Road II, Shanghai 200025, People's Republic of China
| | - Sai-Juan Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine (SJTUSM)197, Ruijin Road II, Shanghai 200025, People's Republic of China
| | - Zhu Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine (SJTUSM)197, Ruijin Road II, Shanghai 200025, People's Republic of China
- Author for correspondence ()
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31
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Abstract
Research has been increasing in recent years into the application of stem cell biology to clinical medicine, particularly its role in the evolution and metastasis of tumours. Stem cells may be the target cell for malignant transformation, and tumour formation could be considered a disorder of stem cell self-renewal pathways. Cancer stem cells have been identified in acute myeloid leukaemia and in breast and central nervous system tumours. Cancer stem cells may have a specific role in tumour metastasis, and their understanding may provide insights into the development of predictive and prognostic markers and specific therapeutic interventions.
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Affiliation(s)
- John B Spillane
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
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32
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Abstract
Mouse models of acute promyelocytic leukemia have been generated through transgenic, knock-in, retroviral, and xenograft strategies. These models have been used to elucidate mechanisms underlying leukemogenesis. Among the areas investigated are the role of reciprocal fusions; effects of target cells, expression levels, and mouse strains; cooperating events; and restrictive and permissive factors. These models have also been used to gain insight into the effects of the immune system on leukemic cells and the mechanism of response to retinoic acid. Furthermore, preclinical studies utilizing these mice have advanced therapy for myeloid leukemia.
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Affiliation(s)
- S C Kogan
- Department of Laboratory Medicine and Comprehensive Cancer Center, University of California, San Francisco, Room S-864, 513 Parnassus Avenue, San Francisco, CA 94143-0100, USA.
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33
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Ikeda A, Shankar DB, Watanabe M, Tamanoi F, Moore TB, Sakamoto KM. Molecular targets and the treatment of myeloid leukemia. Mol Genet Metab 2006; 88:216-24. [PMID: 16678459 DOI: 10.1016/j.ymgme.2006.03.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2005] [Revised: 03/16/2006] [Accepted: 03/16/2006] [Indexed: 10/24/2022]
Abstract
Leukemia is a multistep process involving accumulation of genetic alterations over time. These genetic mutations destroy the delicate balance between cell proliferation, differentiation, and apoptosis. Traditional approaches to treatment of leukemia involve chemotherapy, radiation, and bone marrow transplantation. In recent years, specific targeted therapies have been developed for the treatment of leukemia. The success of treatment of acute promyelocytic leukemia with All Trans Retinoic Acid (ATRA) and CML with imatinib have lead to increased efforts to identify targets that can be inhibited by small molecules for treatment of hematological malignancies. In this review, we describe the current advances in the development of targeted therapy in acute myeloid leukemia.
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Affiliation(s)
- A Ikeda
- Division of Hematology/Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, and Mattel Children's Hospital, Jonsson Comprehensive Cancer Center, USA
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34
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Chan IT, Kutok JL, Williams IR, Cohen S, Moore S, Shigematsu H, Ley TJ, Akashi K, Le Beau MM, Gilliland DG. Oncogenic K-ras cooperates with PML-RAR alpha to induce an acute promyelocytic leukemia-like disease. Blood 2006; 108:1708-15. [PMID: 16675706 PMCID: PMC1895511 DOI: 10.1182/blood-2006-04-015040] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Most patients with acute promyelocytic leukemia (APL) express PML-RAR alpha, the fusion product of t(15;17)(q22;q11.2). Transgenic mice expressing PML-RAR alpha develop APL with long latency, low penetrance, and acquired cytogenetic abnormalities. Based on observations that 4% to 10% of APL patients harbor oncogenic ras mutations, we coexpressed oncogenic K-ras from its endogenous promoter with PML-RAR alpha to generate a short-latency, highly penetrant mouse model of APL. The APL disease was characterized by splenomegaly, leukocytosis, extramedullary hematopoiesis (EMH) in spleen and liver with an increased proportion of immature myeloperoxidase-expressing myeloid forms; transplantability to secondary recipients; and lack of cytogenetic abnormalities. Bone marrow cells showed enhanced self-renewal in vitro. This model establishes a role for oncogenic ras in leukemia pathogenesis and thus validates the oncogenic RAS signaling pathway as a potential target for therapeutic inhibition in leukemia patients. This mouse model should be useful for investigating signaling pathways that promote self-renewal in APL and for testing the in vivo efficacy of RAS signaling pathway inhibitors in conjunction with other targeted therapies such as ATRA (all trans retinoic acid) and arsenic trioxide.
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MESH Headings
- Animals
- Bone Marrow/pathology
- Flow Cytometry
- Genes, ras
- Humans
- Karyotyping
- Leukemia, Promyelocytic, Acute/genetics
- Leukemia, Promyelocytic, Acute/mortality
- Leukemia, Promyelocytic, Acute/pathology
- Leukemia, Promyelocytic, Acute/physiopathology
- Liver/pathology
- Mice
- Mice, Transgenic
- Oncogene Proteins, Fusion/genetics
- Spleen/pathology
- Survival Analysis
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Affiliation(s)
- Iris T Chan
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
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35
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Santana BAA, Pintão MC, Abreu e Lima RS, Scheucher PS, Santos GAS, Garcia AB, Falcão RP, Rego EM. Asynchronous expression of myeloid antigens in leukemic cells in a PML/RARalpha transgenic mouse model. Braz J Med Biol Res 2006; 39:615-20. [PMID: 16648899 DOI: 10.1590/s0100-879x2006000500008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Acute promyelocytic leukemia (APL) is characterized by the expansion of blasts that resemble morphologically promyelocytes and harbor a chromosomal translocation involving the retinoic acid receptor alpha (RARalpha) and the promyelocytic leukemia (PML) genes on chromosomes 17 and 15, respectively. The expression of the PML/RARalpha fusion gene is essential for APL genesis. In fact, transgenic mice (TM) expressing PML/RARalpha develop a form of leukemia that mimics the hematological findings of human APL. Leukemia is diagnosed after a long latency (approximately 12 months) during which no hematological abnormality is detected in peripheral blood (pre-leukemic phase). In humans, immunophenotypic analysis of APL blasts revealed distinct features; however, the precise immunophenotype of leukemic cells in the TM model has not been established. Our aim was to characterize the expression of myeloid antigens by leukemic cells from hCG-PML/RARalpha TM. In this study, TM (N = 12) developed leukemia at the mean age of 13.1 months. Morphological analysis of bone marrow revealed an increase of the percentage of immature myeloid cells in leukemic TM compared to pre-leukemic TM and wild-type controls (48.63 +/- 16.68, 10.83 +/- 8.11, 7.4 +/- 5.46%, respectively; P < 0.05). Flow cytometry analysis of bone marrow and spleen from leukemic TM identified the asynchronous co-expression of CD34, CD117, and CD11b. This abnormal phenotype was rarely detected prior to the diagnosis of leukemia and was present at similar frequencies in hematologically normal TM and wild-type controls of different ages. The present results demonstrate that, similarly to human APL, leukemic cells from hCG-PML/RARalpha TM present a specific immunophenotype.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/immunology
- Bone Marrow/immunology
- Bone Marrow/pathology
- Cathepsin G
- Cathepsins
- Flow Cytometry
- Genotype
- Immunophenotyping
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Promyelocytic, Acute/genetics
- Leukemia, Promyelocytic, Acute/immunology
- Mice
- Mice, Transgenic
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/immunology
- Serine Endopeptidases
- Spleen/immunology
- Spleen/pathology
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Affiliation(s)
- B A A Santana
- Divisão de Hematologia e Centro de Terapia Celular, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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36
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Wang YA, Shen K, Ishida Y, Wang Y, Kakizuka A, Brooks SC. Induction of murine leukemia and lymphoma by dominant negative retinoic acid receptor alpha. Mol Carcinog 2006; 44:252-61. [PMID: 16273555 DOI: 10.1002/mc.20144] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Acute promyelocytic leukemia (APL) is invariably associated with chromosomal translocation to retinoic acid receptor alpha (RARalpha) locus. In a vast majority of cases, RARalpha translocates to and fuses with the promyelocytic leukemia (PML) gene. It was thought that the fusion protein PML-RARalpha acts as a double dominant negative mutant to inhibit the PML and RARalpha signaling. In an attempt to study the physiological role of retinoic acid in mammary gland development, we created a transgenic model system expressing a dominant negative RARalpha under the regulation of murine mammary tumor viral promoter. We found that the transgene was also targeted to the lymphoid system in addition to mammary gland. Here we showed that dominant negative RARalpha induced acute lymphoblastic leukemia and lymphoma development in the transgenic mice. Retinoic acid blocked tumor development ex vivo through induction of apoptosis. Thus, our results suggested that disruption of RARalpha signaling was the first essential step in the development of APL in vivo.
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Affiliation(s)
- Y Alan Wang
- Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA
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37
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Haneline LS, White H, Yang FC, Chen S, Orschell C, Kapur R, Ingram DA. Genetic reduction of class IA PI-3 kinase activity alters fetal hematopoiesis and competitive repopulating ability of hematopoietic stem cells in vivo. Blood 2005; 107:1375-82. [PMID: 16239435 PMCID: PMC1895408 DOI: 10.1182/blood-2005-05-1985] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Class I(A) phosphatidylinositol-3 kinase (PI-3K) is a lipid kinase, which is activated in blood cells by hematopoietic growth factors. In vitro experiments using chemical inhibitors of PI-3K suggest that this kinase is potentially important for hematopoietic stem and progenitor cell (HSC/P) function, and recent studies identify PI-3K as a therapeutic target in treating different leukemias and lymphomas. However, the role of PI-3K in regulating fetal liver or adult hematopoiesis in vivo is unknown. Therefore, we examined PI-3K-deficient embryos generated by a targeted deletion of the p85alpha and p85beta regulatory subunits of PI-3K (p85alpha-/-p85beta+/-). The absolute frequency and number of hematopoietic progenitor cells were reduced in p85alpha-/- p85beta+/- fetal livers compared with wild-type (WT) controls. Further, p85alpha-/-p85beta+/- fetal liver hematopoietic stem cells (HSCs) had decreased multilineage repopulating ability in vivo compared with WT controls in competitive repopulation assays. Finally, purified p85alpha-/-p85beta+/- c-kit+ cells had a decrease in proliferation in response to kit ligand (kitL), a growth factor important for controlling HSC function in vivo. Collectively, these data identify PI-3K as an important regulator of HSC function and potential therapeutic target in treating leukemic stem cells.
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Affiliation(s)
- Laura S Haneline
- Indiana University School of Medicine, Herman B. Wells Center for Pediatric Research, Indianapolis, IN 46202, USA
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38
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Lallemand-Breitenbach V, Zhu J, Kogan S, Chen Z, de Thé H. Opinion: how patients have benefited from mouse models of acute promyelocytic leukaemia. Nat Rev Cancer 2005; 5:821-7. [PMID: 16175176 DOI: 10.1038/nrc1719] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
One of the challenges of studying anticancer therapies is that effects observed in cell lines or mouse models are not always good indicators of clinical trial results. The mouse model of acute promyelocytic leukaemia has bucked this trend, as targeted therapies such as retinoic acid and arsenic induce differentiation and clearance of leukaemia cells in both mice and humans. This mouse model has also provided important mechanistic insights into the combinatorial effects of these agents and has promoted combined therapies that have shown recent success in the clinic.
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Affiliation(s)
- Valérie Lallemand-Breitenbach
- Université de Paris, CNRS UMR 7151, Université de Paris VII, Equipe Labellisée de la Ligue contre le Cancer, Hôpital St. Louis, 1 Avenue C. Vellefaux, 75475 Paris CEDEX 10, France
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39
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Walter MJ, Park JS, Ries RE, Lau SKM, McLellan M, Jaeger S, Wilson RK, Mardis ER, Ley TJ. Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML-RARalpha. Proc Natl Acad Sci U S A 2005; 102:12513-8. [PMID: 16113082 PMCID: PMC1188022 DOI: 10.1073/pnas.0504247102] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PU.1 is a member of the ETS family of transcription factors that is known to be important for hematopoietic development. Recently, haploinsufficiency for PU.1 has been shown to cause a shift in myelomonocytic progenitor fate toward the myeloid lineage. We have previously shown that transgenic mice expressing PML-RARalpha (PR) and RARalpha-PML frequently develop acute promyelocytic leukemia (APL) in association with a large (>20 Mb) interstitial deletion of chromosome 2 that includes PU.1. To directly assess the relevance of levels of expression of PU.1 for leukemia progression, we bred hCG-PR mice with PU.1+/- mice and assessed their phenotype. Young, nonleukemic hCG-PR x PU.1+/- mice developed splenomegaly because of the abnormal expansion of myeloid cells in their spleens. hCG-PR x PU.1+/- mice developed a typical APL syndrome after a long latent period, but the penetrance of disease was 84%, compared with 7% in hCG-PR x PU.1+/+ mice (P < 0.0001). The residual PU.1 allele in hCG-PR x PU.1+/- APL cells was expressed, and complete exonic resequencing revealed no detectable mutations in nine of nine samples. However, PR expression in U937 myelomonocytic cells and primary murine myeloid bone marrow cells caused a reduction in PU.1 mRNA levels. Therefore, the loss of one copy of PU.1 through a deletional mechanism, plus down-regulation of the residual allele caused by PR expression, may synergize to expand the pool of myeloid progenitors that are susceptible to transformation, increasing the penetrance of APL.
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MESH Headings
- Animals
- Chromosome Deletion
- Down-Regulation
- Gene Expression
- Humans
- Leukemia, Promyelocytic, Acute/etiology
- Leukemia, Promyelocytic, Acute/genetics
- Leukemia, Promyelocytic, Acute/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Myeloid Progenitor Cells/pathology
- Neoplasm Proteins/genetics
- Oncogene Proteins, Fusion/genetics
- Phenotype
- Proto-Oncogene Proteins/deficiency
- Proto-Oncogene Proteins/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Splenomegaly/etiology
- Splenomegaly/genetics
- Splenomegaly/pathology
- Trans-Activators/deficiency
- Trans-Activators/genetics
- U937 Cells
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Affiliation(s)
- Matthew J Walter
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA
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40
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Abstract
Acute myelogenous leukemia (AML) is characterized by the accumulation of immature cells due to disturbed differentiation and proliferation of the myeloid lineage. Genetic alterations affecting transcription factors and receptor tyrosine kinases have been identified in AML and causally linked to the disease. The goal of this review is to address the role of the different genetic alterations in self-renewal and proliferation and to discuss the cellular background in which these events occur during the pathogenesis of AML. Data from AML samples, clinical studies and mouse models for AML will be used to support the different theories regarding the leukemogenesis of AML. Finally, this review wants to highlight the implication of these findings for the therapy of AML.
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Affiliation(s)
- J Cammenga
- Department of Molecular Pathology, Heinrich-Pette-Institute for Virology and Experimental Immunology, Hamburg, Germany.
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41
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Du Y, Jenkins NA, Copeland NG. Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. Blood 2005; 106:3932-9. [PMID: 16109773 PMCID: PMC1895096 DOI: 10.1182/blood-2005-03-1113] [Citation(s) in RCA: 163] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Retroviruses can induce hematopoietic disease via insertional mutagenesis of cancer genes and provide valuable molecular tags for cancer gene discovery. Here we show that insertional mutagenesis can also identify genes that promote the immortalization of hematopoietic cells, which normally have only limited self-renewal. Transduction of mouse bone marrow cells with replication-incompetent murine stem cell virus (MSCV) expressing only neo, followed by serial passage in liquid culture containing stem cell factor (SCF) and interleukin-3 (IL-3), produced immortalized immature myeloid cell lines with neutrophil and macrophage differentiation potential in about 50% of the infected cultures. More than half of the lines have MSCV insertions at Evi1 or Prdm16. These loci encode transcription factor homologs and are validated human myeloid leukemia genes. Integrations are located in intron 1 or 2, where they promote expression of truncated proteins lacking the PRDI-BF1-RIZ1 homologous (PR) domain, similar to what is observed in human leukemias with EVI1 or PRDM16 mutations. Evi1 overexpression alone appears sufficient to immortalize immature myeloid cells and does not seem to require any other cooperating mutations. Genes identified by insertional mutagenesis by their nature could also be involved in immortalization of leukemic stem cells, and thus represent attractive drug targets for treating cancer.
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Affiliation(s)
- Yang Du
- Mouse Cancer Genetics Program, National Cancer Institute, Center for Cancer Research, Frederick, MD 21702, USA
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42
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Bai L, Ni HM, Chen X, DiFrancesca D, Yin XM. Deletion of Bid impedes cell proliferation and hepatic carcinogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 166:1523-32. [PMID: 15855651 PMCID: PMC1606404 DOI: 10.1016/s0002-9440(10)62368-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mechanisms that control the proliferation capability of the initiated cells during hepatocarcinogenesis are still largely unclear. We investigated the role of a pro-death Bcl-2 family protein, Bid, in liver tumor development using a neonatal diethylnitrosamine model. Diethylnitrosamine was administrated to 15-day-old wild-type and bid-null mice. The development of microfoci at the early stage and of gross tumors at the later stage was compared between the two groups of mice. Both microfoci and gross tumor development were significantly retarded in the bid-null mice, despite reduced cell death as measured by TUNEL staining. Further studies indicated that there were significantly less proliferating cells in diethylnitrosamine-treated bid-null livers. The regulation of cell proliferation by Bid was confirmed in two other systems not involving carcinogenesis. Hepatocyte proliferation following partial hepatectomy and T lymphocyte proliferation following anti-CD3 stimulation were both retarded in bid-null mice. Thus, these studies revealed a previously undisclosed function of Bid in regulating cell proliferation, which can be important to tumor development. Furthermore, the role of Bid in promoting hepatocarcinogenesis is in contrast to its reported role in suppressing myeloid leukemia and thus suggests an organ- and/or etiology-specific role of the Bcl-2 family proteins in regulating oncogenesis.
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Affiliation(s)
- Li Bai
- Department of Pathology, University of Pittsburgh School of Medicine, Scaife Hall, 7th Floor, Room S739, 3550 Terrace Street, Pittsburgh, Pennsylvania 15261, USA
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43
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Shao QS, Ye ZY, Ling ZQ, Ke JJ. Cell cycle arrest and apoptotic cell death in cultured human gastric carcinoma cells mediated by arsenic trioxide. World J Gastroenterol 2005; 11:3451-6. [PMID: 15948253 PMCID: PMC4316002 DOI: 10.3748/wjg.v11.i22.3451] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of arsenic trioxide on human gastric cancer cell line MKN45 with respect to both cytotoxicity and induction of apoptosis in vitro.
METHODS: MKN45 cells were treated with arsenic trioxide (As2O3) at the concentration of 1, 5, and 10 µmol/L, respectively, for three successive days. Cell growth and proliferation were observed by cell counting and trypan blue exclusion. Cytotoxicity of As2O3 was determined by MTT assay. Morphologic changes were studied with light microscopy. Flow cytometry was used to assay cell DNA distribution and apoptotic cells were confirmed with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and DNA electrophoresis.
RESULTS: The growth of MKN45 cells was significantly inhibited by As2O3 which was confirmed by colony-forming assay. After 7 d of culture with various concentrations of As2O3, colony-forming capacity of MKN45 cells decreased with As2O3 increment in comparison with that of control group. The inhibitory rate of colony-formation was 38.5%, 99.1%, and 99.5% when the concentration of As2O3 was 1, 5, and 10 μmol/L in culture medium, respectively. The cell number of a single colony in drug treatment groups was less than that of control group. The cell-killing rate of As2O3 to MKN45 cells was both dose- and time-dependent with an IC50 of (11.05±0.25) µmol/L. After incubation in 10 μmol/L As2O3 for 24 h, the cell-killing rate was 27.1%, and it was close to 50% after 48 h. The results showed that As2O3 induced time- and dose-dependent apoptosis in MKN45 cells, blocked at G2/M phase. The apoptotic peak (sub-G1 phase) appeared and cell apoptotic rate in MKN45 cells was 18.3-32.5% after treatment by 10 μmol/L As2O3 for 48 h. The percentage of G2/M cell of the experimental groups was 2.0-5.0 times than that of the control group. Gel electrophoresis of DNA from cells treated with each concentration of As2O3 for 48 h revealed a “ladder” pattern, indicating preferential DNA degradation at the internucleosomal, linker DNA sections. TUNEL also demonstrated strand breaks in DNA of MKN45 cells treated with As2O3, while control cells showed negative labeling.
CONCLUSION: As2O3 can induce apoptosis of human gastric carcinoma cells MKN45, which is the basis of its effectiveness. It shows great potential in the treatment of gastric carcinoma.
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Affiliation(s)
- Qin-Shu Shao
- Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang Province, China
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44
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McCormack E, Bruserud O, Gjertsen BT. Animal models of acute myelogenous leukaemia - development, application and future perspectives. Leukemia 2005; 19:687-706. [PMID: 15759039 DOI: 10.1038/sj.leu.2403670] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
From the early inception of the transplant models through to contemporary genetic and xenograft models, evolution of murine leukaemic model systems have been critical to our general comprehension and treatment of cancer, and, more specifically, disease states such as acute myelogenous leukaemia (AML). However, even with modern advances in therapeutics and molecular diagnostics, the majority of AML patients die from their disease. Thus, in the absence of definitive in vitro models which precisely recapitulate the in vivo setting of human AMLs and failure of significant numbers of new drugs late in clinical trials, it is essential that murine AML models are developed to exploit more specific, targeted therapeutics. While various model systems are described and discussed in the literature from initial transplant models such as BNML and spontaneous murine leukaemia virus models, to the more definitive genetic and clinically significant NOD/SCID xenograft models, there exists no single compendium which directly assesses, reviews or compares the relevance of these models. Thus, the function of this article is to provide clinicians and experimentalists a chronological, comprehensive appraisal of all AML model systems, critical discussion on the elucidation of their roles in our understanding of AML and consideration to their efficacy in the development of AML chemotherapeutics.
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Affiliation(s)
- E McCormack
- Hematology Section, Institute of Medicine, University of Bergen, Bergen, Norway
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Abstract
The proto-oncogene BCL-2 was discovered with the cloning of the t(14;18) chromosomal translocation responsible for human follicular lymphoma. Since then other members of the Bcl-2 family of cell death regulators have been identified and their roles in cell death, normal lymphoid development, and lymphoid neoplasia have been characterized. Bcl-2 family members are important in tumor initiation, progression, and response to chemotherapy, and altered expression levels of various members serve as prognostic markers in many lymphoid malignancies. There are promising cancer therapeutics now targeted at members of the Bcl-2 family.
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Affiliation(s)
- Michael C Wei
- Department of Medicine, Children's Hospital Boston, Massachusetts 02125, USA.
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Zhu J, Zhou J, Peres L, Riaucoux F, Honoré N, Kogan S, de Thé H. A sumoylation site in PML/RARA is essential for leukemic transformation. Cancer Cell 2005; 7:143-53. [PMID: 15710327 DOI: 10.1016/j.ccr.2005.01.005] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2004] [Revised: 06/18/2004] [Accepted: 01/12/2005] [Indexed: 11/15/2022]
Abstract
Pathogenesis of acute promyelocytic leukemia (APL) has been proposed to involve transcriptional repression through enhanced corepressors binding onto RARA moieties of PML/RARA homodimers. Unexpectedly, we show that the K160 sumoylation site in the PML moiety of PML/RARA is required for efficient immortalization/differentiation arrest ex vivo, implying that RARA homodimerization is insufficient to fully immortalize primary hematopoietic progenitor cells. Similarly, PML/RARAK160R transgenic mice develop myeloproliferative syndromes, but never APL. The Daxx repressor no longer binds PML/RARAK160R, but fusion of these two proteins restores the differentiation block ex vivo. Thus, transcriptional repression dependent on a specific sumoylation site in PML is critical for the APL phenotype, while forced RARA dimerization could control expansion of the myeloid compartment.
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Affiliation(s)
- Jun Zhu
- CNRS UPR 9051, laboratoire associé N11 du comité de Paris de la Ligue contre le Cancer, affilié à l'Université de Paris VII, Hôpital St. Louis, 1 avenue Claude Vellefaux, 75475 Paris, Cedex 10, France
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Walter MJ, Park JS, Lau SKM, Li X, Lane AA, Nagarajan R, Shannon WD, Ley TJ. Expression profiling of murine acute promyelocytic leukemia cells reveals multiple model-dependent progression signatures. Mol Cell Biol 2004; 24:10882-93. [PMID: 15572690 PMCID: PMC533966 DOI: 10.1128/mcb.24.24.10882-10893.2004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Leukemia results from the expansion of self-renewing hematopoietic cells that are thought to contain mutations that contribute to disease initiation and progression. Studies of the gene expression profiles of human acute myeloid leukemia samples has allowed their classification based on the presence of translocations and French-American-British subtypes, but it is not yet clear whether their molecular signatures reflect the initiating mutations or mutations acquired during progression. To begin to address this question, we examined the expression profiles of normal murine promyelocyte-enriched samples, nontransformed murine promyelocytes expressing human promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion gene, and primary acute promyelocytic leukemia cells. The expression profile of nontransformed cells expressing PML-RARalpha was remarkably similar to that of wild-type promyelocytes. In contrast, the expression profiles of fully transformed cells from three acute promyelocytic leukemia model systems were all different, suggesting that the expression signature of acute promyelocytic leukemia cells reflects the genetic changes that contributed to progression. To further evaluate these progression events, we compared two high-penetrance acute promyelocytic leukemia models that both commonly acquire an interstitial deletion of chromosome 2 during progression. The two models exhibited distinct gene expression profiles, suggesting that the dominant molecular signatures of murine acute promyelocytic leukemia can be influenced by several independent progression events.
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MESH Headings
- Animals
- Disease Models, Animal
- Disease Progression
- Gene Deletion
- Gene Dosage
- Gene Expression Profiling
- Gene Expression Regulation, Leukemic
- Humans
- Leukemia, Promyelocytic, Acute/genetics
- Leukemia, Promyelocytic, Acute/metabolism
- Leukemia, Promyelocytic, Acute/pathology
- Mice
- Mice, Transgenic
- Neoplasm Proteins/genetics
- Oncogene Proteins, Fusion/genetics
- Penetrance
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Affiliation(s)
- Matthew J Walter
- Division of Oncology, Section of Stem Cell Biology, Campus Box 8007, 660 South Euclid Ave., St. Louis, MO 63110-1093, USA
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Heiser D, Labi V, Erlacher M, Villunger A. The Bcl-2 protein family and its role in the development of neoplastic disease. Exp Gerontol 2004; 39:1125-35. [PMID: 15288687 DOI: 10.1016/j.exger.2004.04.011] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2004] [Revised: 04/28/2004] [Accepted: 04/30/2004] [Indexed: 01/09/2023]
Abstract
Programmed cell death is the physiological process responsible for shaping organs during embryogenesis, maintaining tissue homeostasis and allowing controlled deletion of potentially harmful cells within the adult organism. The genetics of apoptosis are well conserved in all metazoans and although the evolution of humans and worms separated more than 600 million years ago, basic signaling concepts in apoptosis are highly related in both species. More crucial to humans than worms is the fact that abnormalities in cell death control can contribute to the development of cancer. While C.elegans can easily survive with additional somatic cells that should normally be deleted during development humans may suffer pathological consequences, ranging from tumorigenesis to autoimmunity, as a result of mutations in cell death regulatory genes. Despite the high degree of evolutionary conservation in cell death control, apoptosis signaling in mammals is much more complex than in C.elegans. In mammalian cells, programmed cell death can be induced either by ligand-mediated activation of certain members of the tumor necrosis factor receptor family--so-called 'death receptors'--such as Fas (CD95/Apo-1) and TRAIL or it can be induced in a cell autonomous manner in response to certain stress signals by pro-apoptotic members of the Bcl-2 family. In this review, we focus on general concepts of how the Bcl-2 protein family regulates cell death and how deregulation of this 'intrinsic' apoptotic signaling pathway impinges on the pathogenesis of malignant disease, the major cause of death in the aging population.
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Affiliation(s)
- Dietmar Heiser
- Institute of Pathophysiology, University of Innsbruck Medical School, Fritz-Pregl-Str. 3, A-6020 Innsbruck, Austria
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Abstract
Studies utilizing experimental animals, epidemiological approaches, cellular models, and clinical trials all provide evidence that retinoic acid and some of its synthetic derivatives (retinoids) are useful pharmacological agents in cancer therapy and prevention. In this chapter, we first review the current knowledge of retinoic acid receptors (RARs) and their role in mediating the actions of retinoic acid. We then focus on a discussion of RARalpha and acute promyelocytic leukemia followed by a discussion of the role of RARs, in particular RARbeta expression, in other cancer types. Loss of normal RAR function in the presence of physiological levels of RA (either due to alterations in the protein structure or level of expression) is associated with a variety of different cancers. In some cases treatment with pharmacological doses of RA can be effective.
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Affiliation(s)
- Dianne Robert Soprano
- Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
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Abstract
Two fundamental problems in cancer research are identification of the normal cell within which cancer initiates and identification of the cell type capable of sustaining the growth of the neoplastic clone. There is overwhelming evidence that virtually all cancers are clonal and represent the progeny of a single cell. What is less clear for most cancers is which cells within the tumor clone possess tumorigenic or 'cancer stem cell' (CSC) properties and are capable of maintaining tumor growth. The concept that only a subpopulation of rare CSC is responsible for maintenance of the neoplasm emerged nearly 50 years ago. Testing of this hypothesis is most advanced for the hematopoietic system due to the establishment of functional in vitro and in vivo assays for stem and progenitor cells at all stages of development. This body of work led to conclusive proof for CSC with the identification and purification of leukemic stem cells capable of repopulating NOD/SCID mice. This review will focus on the historical development of the CSC hypothesis, the mechanisms necessary to subvert normal developmental programs, and the identification of the cell in which these leukemogenic events first occur.
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Affiliation(s)
- Jennifer K Warner
- Division of Cell and Molecular Biology, University Health Network, University of Toronto, 620 University Ave, ON M5G 2C1, Canada
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