期刊
LEUKEMIA
卷 26, 期 10, 页码 2224-2232出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2012.95
关键词
microRNA; B-cell acute lymphoblastic leukemia; B-cell differentiation; proliferation
资金
- Fondation pour la Recherche Medicale
- Bayer Science and Education Foundation
- Institut National du Cancer
- Association pour la Recherche sur le Cancer (ARC)
- CITTIL program
- Institut Universitaire de France
B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA, miR-125b-1, is overexpressed in B-ALL cases with the t(11;14)(q24;q32) translocation; therefore, we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was downregulated in B-ALL patients with the t(11; 14)(q24; q32) translocation. Repression of Bright/ARID3a blocked differentiation and conferred a survival advantage to Ba/F3 cells under interleukin-3 starvation. In addition, overexpression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis by blockade of caspase activation by a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis. Leukemia (2012) 26, 2224-2232; doi:10.1038/leu.2012.95
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