Distinct microRNA expression profiles in acute myeloid leukemia with common translocations

Li, Zejuan; Lü, Jun; Sun, Miao; Mi, Shuangli; Zhang, Hao; Luo, Roger T.; Chen, Ping; Wang, Yungui; Yan, Ming; Qian, Zhijian; Neilly, Mary Beth; Jin, Jie; Zhang, Yanming; Bohlander, Stefan K.; Zhang, Dong Er; Larson, Richard A.; Beau, Michelle M. Le; Thirman, Michael J.; Golub, Todd R.; Rowley, Janet D.; Chen, Jianjun

doi:10.1073/pnas.0808266105

Cited by 418 publications

(475 citation statements)

References 60 publications

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“…Several miRNAs play important roles in hematopoiesis and their deregulation can contribute to leukemogenesis (23,(38)(39)(40)(41)(42)(43)(44). However, the mechanisms of action of only a few oncogenic miRNAs have been investigated.…”

Section: Discussionmentioning

confidence: 99%

miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

Bousquet

Zhuang

et al. 2013

Molecular Cancer Research

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The microRNA miR-150, a critical regulator of hematopoiesis, is downregulated in mixed-lineage leukemia (MLL). In this study, miR-150 acts as a potent leukemic tumor suppressor by blocking the oncogenic properties of leukemic cells. By using MLL-AF9-transformed cells, we demonstrate that ectopic expression of miR-150 inhibits blast colony formation, cell growth, and increases apoptosis in vitro. More importantly, ectopic expression of miR-150 in MLL-AF9-transformed cells completely blocked the development of myeloid leukemia in transplanted mice. Furthermore, gene expression profiling revealed that miR-150 altered the expression levels of more than 30 "stem cell signature" genes and many others that are involved in critical cancer pathways. In addition to the known miR-150 target Myb, we also identified Cbl and Egr2 as bona fide targets and shRNA-mediated suppression of these genes recapitulated the pro-apoptotic effects observed in leukemic cells with miR-150 ectopic expression.In conclusion, we demonstrate that miR-150 is a potent leukemic tumor suppressor that regulates multiple oncogenes.Implications: These data establish new, key players for the development of therapeutic strategies to treat MLL-AF9-related leukemia. Mol Cancer Res; 11(8); 912-22. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

Bousquet

Zhuang

et al. 2013

Molecular Cancer Research

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“…The high expression of miR-126/miR-126* in inv(16) and t(8;21)-positive AML patients (Table 2) prompted Li et al 21 to functionally study these miRNAs. Enforced expression of miR-126 and its star strand in AML cell lines inhibited the apoptotic potential and facilitated cell survival.…”

Section: Oncogenic Mirnasmentioning

confidence: 99%

“…High expression of another set of miRNAs including miR-382 was unique for t(15;17)/PML-RARa-positive AML. 18,20 MLL-rearranged AML cases, the oncogenic miR-17-92 cluster was upregulated 21,34,32 whereas the tumor-suppressor miR-29 was downregulated (Table 2). 19,23 MiRNA expression levels are also associated with molecular subtypes of AML, the mutational status and associated gene expression pattern in AML (Table 2).…”

Section: Aberrant Mirna Expression Characterizes Different Cytogenetimentioning

confidence: 99%

“…22 Adult acute myeloid leukemia (AML) patients with t(8;21)/ AML1-ETO or inv(16)/CBFb-MYH11 were distinguished from other AML patients by high and low expression of miR-126/126* (ref. 21) and let-7b/c, 20 respectively (Table 2). High expression of another set of miRNAs including miR-382 was unique for t(15;17)/PML-RARa-positive AML.…”

Section: Aberrant Mirna Expression Characterizes Different Cytogenetimentioning

confidence: 99%

“…These studies showed that leukemic cells of acute leukemia patients have different miRNA expression patterns than normal hematopoietic cells. [18][19][20][21] Quantitative analysis of 397 miRNAs revealed that leukemic cells of pediatric precursor B-ALL patients have different miRNA expression profiles than samples of normal bone marrow and CD34 þ sorted cells. 22 Moreover, miRNAs were significantly differentially expressed between T-ALL cases and normal thymocytes.…”

Section: Aberrant Mirna Expression Characterizes Different Cytogenetimentioning

confidence: 99%

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MicroRNAs in acute leukemia: from biological players to clinical contributors

2011

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MicroRNAs (miRNAs) are involved in the management of hematopoiesis. As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. We here comprehensively discuss miRNAs found discriminative for cytogenetic and molecular subtypes of acute leukemia. These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified by high-throughput sequencing with yet unknown function. Furthermore, forces are outlined that drive aberrant miRNA function, which include genetic abnormalities (for example, deletions, translocations and mutations) and epigenetic aberrations (for example, aberrant DNA methylation or histone modifications). Interestingly, leukemia-silenced miRNAs can be re-expressed upon treatment with de-methylating agents. Targeting miRNA expression may serve a therapeutical role, albeit at present this way of targeted therapy is in its infancy. However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia.

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Role of TGF‐β1/miR‐382‐5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis

et al. 2018

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Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by an excessive production of pro‐inflammatory cytokines resulting in chronic inflammation and genomic instability. Besides the driver mutations in JAK2,MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR‐382‐5p in PMF CD34+ cells. In order to unveil the mechanistic details of the role of miR‐382‐5p in pathogenesis of PMF, we performed gene expression profiling of CD34+ cells overexpressing miR‐382‐5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR‐382‐5p. Subsequently, we confirmed miR‐382‐5p/SOD2 interaction by luciferase assay and we showed that miR‐382‐5p overexpression in CD34+ cells causes the decrease in SOD2 activity leading to reactive oxygen species (ROS) accumulation and oxidative DNA damage. In addition, our data indicate that inhibition of miR‐382‐5p in PMF CD34+ cells restores SOD2 function, induces ROS disposal, and reduces DNA oxidation. Since the pro‐inflammatory cytokine transforming growth factor‐β1 (TGF‐β1) is a key player in PMF pathogenesis, we further investigated the effect of TGF‐β1 on ROS and miR‐382‐5p levels. Our data showed that TGF‐β1 treatment enhances miR‐382‐5p expression and reduces SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF‐β1 signaling in PMF CD34+ cells by galunisertib significantly reduced miR‐382‐5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF‐β1/miR‐382‐5p/SOD2 axis deregulation in PMF cells is linked to ROS overproduction that may contribute to enhanced oxidative stress and inflammation. Our results suggest that galunisertib may represent an effective drug reducing abnormal oxidative stress induced by TGF‐β1 in PMF patients.Database linkingGEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464.

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Distinct microRNA expression profiles in acute myeloid leukemia with common translocations

Cited by 418 publications

References 60 publications

miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

MicroRNAs in acute leukemia: from biological players to clinical contributors

Role of TGF‐β1/miR‐382‐5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis

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