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

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

Author Mi, Shuangli Google Scholar
Li, Zejuan Google Scholar
Chen, Ping Google Scholar
He, Chunjiang Google Scholar
Cao, Donglin Google Scholar
Elkahloun, Abdel Google Scholar
Lu, Jun Google Scholar
Pelloso, Luís Arthur Flores Autor UNIFESP Google Scholar
Wunderlich, Mark Google Scholar
Huang, Hao Google Scholar
Luo, Roger T. Google Scholar
Sun, Miao Google Scholar
He, Miao Google Scholar
Neilly, Mary Beth Google Scholar
Zeleznik-Le, Nancy J. Google Scholar
Thirman, Michael J. Google Scholar
Mulloy, James C. Google Scholar
Liu, Paul P. Google Scholar
Rowley, Janet D. Google Scholar
Chen, Jianjun Google Scholar
Institution Univ Chicago
Yale Univ
Univ Cincinnati
Loyola Univ
So Med Univ
Universidade Federal de São Paulo (UNIFESP)
China Med Univ
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. More importantly, we show that 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.
Keywords cell apoptosis and viability
colony-forming/replating assay
MLL binding
gene regulation
miRNA target
Language English
Sponsor Yanamashi University, Japan
National Institutes of Health (NIH)
University of Chicago Cancer Center Pilot
G. Harold and Leila Y. Mathers Charitable Foundation
Leukemia and Lymphoma Society Translational Research
Spastic Paralysis Foundation of the Illinois, Eastern Iowa Branch of Kiwanis International
Intramural Research Program of the National Human Genome Research Institute
National Institutes of Health
Leukemia and Lymphoma Society Specialized Center of Research
Grant number Yanamashi University, Japan: KOPN1
Yanamashi University, Japan: KOCL33
Yanamashi University, Japan: KOCL44
Yanamashi University, Japan: KOCL45
Yanamashi University, Japan: KOCL48
Yanamashi University, Japan: KOCL50
Yanamashi University, Japan: KOCL51
Yanamashi University, Japan: KOCL69
National Institutes of Health (NIH): CA127277
Leukemia and Lymphoma Society Specialized Center of Research: NIH PO1CA105049
: CA118319
Date 2010-02-23
Published in Proceedings of the National Academy of Sciences of the United States of America. Washington: Natl Acad Sciences, v. 107, n. 8, p. 3710-3715, 2010.
ISSN 0027-8424 (Sherpa/Romeo, impact factor)
Publisher Natl Acad Sciences
Extent 3710-3715
Origin http://dx.doi.org/10.1073/pnas.0914900107
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000275130900078
URI http://repositorio.unifesp.br/handle/11600/32274

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