miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia

Ping Chen, Colles Price, Zejuan Li, Yuanyuan Li, Donglin Cao, Anissa Wiley, Chunjiang He, Sandeep Gurbuxani, Rejani B. Kunjamma, Hao Huang, Xi Jiang, Stephen Arnovitz, Mengyi Xu, Gia Ming Hong, Abdel G. Elkahloun, Mary Beth Neilly, Mark Wunderlich, Richard A. Larson, Michelle M. Le Beau, James C. MulloyPaul P. Liu, Janet D. Rowley*, Jianjun Chen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

MicroRNAs (miRNAs), small noncoding RNAs that regulate target gene mRNAs, are known to contribute to pathogenesis of cancers. Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies with various chromosomal and/or molecular abnormalities. AML with chromosomal translocations involving the mixed lineage leukemia (MLL) gene are usually associated with poor survival. In the present study, through a large-scale, genome-wide miRNA expression assay, we show that microRNA-9 (miR-9) is the most specifically up-regulated miRNA in MLL-rearranged AML compared with both normal control and non-MLL-rearranged AML. We demonstrate that miR-9 is a direct target of MLL fusion proteins and can be significantly up-regulated in expression by the latter in human and mouse hematopoietic stem/progenitor cells. Depletion of endogenous miR-9 expression by an appropriate antagomiR can significantly inhibit cell growth/viability and promote apoptosis in human MLL-rearranged AML cells, and the opposite is true when expression of miR-9 is forced. Blocking endogenous miR-9 function by anti-miRNA sponge can significantly inhibit, whereas forced expression of miR-9 can significantly promote, MLL fusion-induced immortalization/transformation of normal mouse bone marrow progenitor cells in vitro. Furthermore, forced expression of miR-9 can significantly promote MLL fusion-mediated leukemogenesis in vivo. In addition, a group of putative target genes of miR-9 exhibited a significant inverse correlation of expression with miR-9 in a series of leukemia sample sets, suggesting that they are potential targets of miR-9 in MLL-rearranged AML. Collectively, our data demonstrate that miR-9 is a critical oncomiR in MLL-rearranged AML and can serve as a potential therapeutic target to treat this dismal disease.

Original languageEnglish (US)
Pages (from-to)11511-11516
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number28
DOIs
StatePublished - Jul 9 2013

ASJC Scopus subject areas

  • General

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