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Published July 23, 2010 | Supplemental Material + Accepted Version
Journal Article Open

MicroRNA-34a Perturbs B Lymphocyte Development by Repressing the Forkhead Box Transcription Factor Foxp1

Abstract

MicroRNAs (miRNAs) can influence lineage choice or affect critical developmental checkpoints during hematopoiesis. We examined the role of the p53-induced microRNA miR-34a in hematopoiesis by gain-of-function analysis in murine bone marrow. Constitutive expression of miR-34a led to a block in B cell development at the pro-B-cell-to-pre-B-cell transition, leading to a reduction in mature B cells. This block appeared to be mediated primarily by inhibited expression of the transcription factor Foxp1. Foxp1 was a direct target of miR-34a in a 3′-untranslated region (UTR)-dependent fashion. Knockdown of Foxp1 by siRNA recapitulated the B cell developmental phenotype induced by miR-34a, whereas cotransduction of Foxp1 lacking its 3′ UTR with miR-34a rescued B cell maturation. Knockdown of miR-34a resulted in increased amounts of Foxp1 and mature B cells. These findings identify a role for miR-34a in connecting the p53 network with suppression of Foxp1, a known B cell oncogene.

Additional Information

© 2010 Elsevier Inc. Received 15 June 2009; revised 11 March 2010; accepted 15 May 2010. Published online: July 1, 2010. Available online 1 July 2010. We would like to thank members of the Baltimore laboratory, K. Dorshkind, and E. Rothenberg for helpful discussions. This work was supported by career development award 1K08CA133521 from the National Cancer Institute and a clinical fellowship training grant from the California Institute of Regenerative Medicine/Eli and Edythe Broad Center for Regenerative Medicine and Stem cell Research at UCLA (D.S.R.), the Irvington Institute Fellowship Program of the Cancer Research Institute and award number K99HL102228 from the National Heart, Lung and Blood Institute (R.M.O.), the graduate research fellowship program of the National Science Foundation (A.A.C.), and National Institutes of Health (1R01AI079243-01; D.B.). D.B. is a member of the scientific advisory board for Regulus Therapeutics, a company developing therapeutics based on microRNA function.

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Accepted Version - nihms217384.pdf

Supplemental Material - mmc1.pdf

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