Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia

Shuangli Mi, Zejuan Li, Ping Chen, Chunjiang He, Donglin Cao, Abdel Elkahloun, Jun Lu, Luis A. Pelloso, Mark Wunderlich, Hao Huang, Roger T. Luo, Miao Sun, Miao He, Mary Beth Neilly, Nancy J. Zeleznik-Le, Michael J. Thirman, James C. Mulloy, Paul P. Liu, Janet D. Rowley, Jianjun Chen

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

MicroRNA (miRNA)-17-92 cluster (miR-17-92), containing seven individual miRNAs, is frequently amplified and overexpressed in lymphomas and various solid tumors. We have found that it is also frequently amplified and the miRNAs are aberrantly overexpressed in mixed lineage leukemia (MLL)-rearranged acute leukemias. Furthermore, we show that MLL fusions exhibit a much stronger direct binding to the locus of this miRNA cluster than does wild-type MLL; these changes are associated with elevated levels of histone H3 acetylation and H3K4 trimethylation and an up-regulation of these miRNAs. We further observe that forced expression of this miRNA cluster increases proliferation and inhibits apoptosis of human cells. Moreimportantly,weshowthat this miRNA cluster can significantly increase colony-forming capacity of normal mouse bone marrow progenitor cells alone and, particularly, in cooperation with MLL fusions. Finally, through combinatorial analysis of miRNA and mRNA arrays of mouse bone marrow progenitor cells transfected with this miRNA cluster and/or MLL fusion gene, we identified 363 potential miR-17-92 target genes that exhibited a significant inverse correlation of expression with the miRNAs. Remarkably, these potential target genes are significantly enriched (P < 0.01; >2-fold) in cell differentiation, hematopoiesis, cell cycle, and apoptosis. Taken together, our studies suggest that overexpression of miR-17-92 cluster in MLL-rearranged leukemias is likely attributed to both DNA copy number amplification and direct up-regulation by MLL fusions, and that the miRNAs in this cluster may play an essential role in the development of MLL-associated leukemias through inhibiting cell differentiation and apoptosis, while promoting cell proliferation, by regulating relevant target genes.

Original languageEnglish (US)
Pages (from-to)3710-3715
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number8
DOIs
StatePublished - Feb 23 2010

Keywords

  • Cell apoptosis and viability
  • Colony-forming/replating assay
  • Gene regulation
  • MLL binding
  • MiRNA target

ASJC Scopus subject areas

  • General

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