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Blood, 15 January 2009, Vol. 113, No. 3, pp. 505-516.
Prepublished online as a Blood First Edition Paper on September 25, 2008; DOI 10.1182/blood-2008-01-136218.
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Submitted January 29, 2008
Accepted September 5, 2008
The c-myb Protooncogene and microRNA (miR)-15a comprise an active autoregulatory feedback loop in human hematopoietic cells
Huiwu Zhao, Anna Kalota, Shenghao Jin, and Alan M. Gewirtz*
Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States
* Corresponding author; email: gewirtz{at}mail.med.upenn.edu.
The c-myb proto-oncogene encodes an obligate hematopoietic cell transcription factor important for lineage commitment, proliferation, and differentiation. Given its critical functions, c-Myb regulatory factors are of great interest but remain incompletely defined. Herein we show that c-Myb expression is subject to post-transcriptional regulation by microRNA (miRNA)-15a. Using a luciferase reporter assay, we found that miR-15a directly binds the 3'-UTR of c-myb mRNA. By transfecting K562 myeloid leukemia cells with a miR-15a mimic, functionality of binding was shown. The mimic decreased c-Myb expression, and blocked the cells in the G1-phase of cell cycle. Exogenous expression of c-myb mRNA lacking the 3'-UTR partially rescued the miR-15a induced cell cycle block. Of interest, the miR-15a promoter contained several potential Myb protein binding sites. Occupancy of one canonical Myb binding site was demonstrated by ChIP analysis, and further shown to be required for miR-15a expression in K562 cells. Finally, in studies employing normal human CD34+ cells, we showed that c-Myb and miR-15a expression were inversely correlated in cells undergoing erythroid differentiation, and that overexpression of miR-15a blocked both erythroid and myeloid colony formation in vitro. In aggregate, these findings suggest the presence of a Myb-miR-15a auto-regulatory feedback loop of potential importance in human hematopoiesis.
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