miR-495 is a tumor-suppressor microRNA down-regulated in MLL-rearranged leukemia

Xi Jiang, Hao Huang, Zejuan Li, Chunjiang He, Yuanyuan Li, Ping Chen, Sandeep Gurbuxani, Stephen Arnovitz, Gia Ming Hong, Colles Price, Haomin Ren, Rejani B. Kunjamma, Mary Beth Neilly, Justin Salat, Mark Wunderlich, Robert K. Slany, Yanming Zhang, Richard A. Larson, Michelle M. Le Beau, James C. MulloyJanet D. Rowley*, Jianjun Chen

*Corresponding author for this work

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies with variable response to treatment. AMLs bearing MLL (mixed lineage leukemia) rearrangements are associated with intermediate or poor survival. MicroRNAs (miRNAs), a class of small noncoding RNAs, have been postulated to be important gene expression regulators virtually in all biological processes, including leukemogenesis. Through a large-scale, genomewide miRNA expression profiling assay of 85 human AML and 15 normal control samples, we show that among 48 miRNAs that are significantly differentially expressed between MLL- and non-MLL-rearranged AML samples, only one (miR-495) is expressed at a lower level in MLL-rearranged AML than in non-MLL-rearranged AML; meanwhile, miR-495 is also significantly down-regulated in MLL-rearranged AML samples compared with normal control samples. Through in vitro colony-forming/replating assays and in vivo bone marrow transplantation studies, we show that forced expression of miR-495 significantly inhibits MLL-fusion-mediated cell transformation in vitro and leukemogenesis in vivo. In human leukemic cells carrying MLL rearrangements, ectopic expression of miR-495 greatly inhibits cell viability and increases cell apoptosis. Furthermore, our studies demonstrate that PBX3 and MEIS1 are two direct target genes of miR-495, and forced expression of either of them can reverse the effects of miR-495 overexpression on inhibiting cell viability and promoting apoptosis of human MLL-rearranged leukemic cells. Thus, our data indicate that miR-495 likely functions as a tumor suppressor in AML with MLL rearrangements by targeting essential leukemia-related genes.

Original languageEnglish (US)
Pages (from-to)19397-19402
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number47
DOIs
StatePublished - Nov 20 2012

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    Jiang, X., Huang, H., Li, Z., He, C., Li, Y., Chen, P., Gurbuxani, S., Arnovitz, S., Hong, G. M., Price, C., Ren, H., Kunjamma, R. B., Neilly, M. B., Salat, J., Wunderlich, M., Slany, R. K., Zhang, Y., Larson, R. A., Le Beau, M. M., ... Chen, J. (2012). miR-495 is a tumor-suppressor microRNA down-regulated in MLL-rearranged leukemia. Proceedings of the National Academy of Sciences of the United States of America, 109(47), 19397-19402. https://doi.org/10.1073/pnas.1217519109