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

• Published in: Immunity (Cambridge, Mass.) Vol. 33; no. 1; pp. 48 - 59
• Main Authors: Rao, Dinesh S., O'Connell, Ryan M., Chaudhuri, Aadel A., Garcia-Flores, Yvette, Geiger, Theresa L., Baltimore, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.07.2010; Elsevier Limited
• Subjects: 3' Untranslated Regions; Animals; Apoptosis; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Bone marrow; Bone Marrow - metabolism; Bone Marrow - pathology; Cell cycle; Cell Line; CELLIMMUNO; Cloning, Molecular; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene expression; Gene loci; Hematopoiesis; Humans; Immune system; Leukemia; Medical research; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; MOLIMMUNO; Plasmids; Precursor Cells, B-Lymphoid - metabolism; Precursor Cells, B-Lymphoid - pathology; Proteins; Radiation Chimera; Repressor Proteins - genetics; Repressor Proteins - metabolism; Rodents; Scholarships & fellowships; Transcription factors; Tumor Suppressor Protein p53 - metabolism; MOLIMMUNO; CELLIMMUNO
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2010.06.013

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. ► Constitutive expression of miR-34a causes a partial block in B cell development ► Foxp1 is a direct target of miR-34a ► Foxp1 loss of function recapitulates effects of miR-34a expression ► miR-34a knockdown results in increased B cells and derepression of Foxp1