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Nature Cell Biology 10, 788–801 (1 July 2008) | doi:10.1038/ncb1741

A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis

Catherine Labbaye , Isabella Spinello , Maria Teresa Quaranta , Elvira Pelosi , Luca Pasquini , Eleonora Petrucci , Mauro Biffoni , Eugenia Rosa Nuzzolo , Monia Billi , Robin Fo|[agrave]| , Ercole Brunetti , Francesco Grignani , Ugo Testa & Cesare Peschle

MicroRNAs (miRNAs or miRs) regulate diverse normal and abnormal cell functions. We have identified a regulatory pathway in normal megakaryopoiesis, involving the PLZF transcription factor, miR-146a and the SDF-1 receptor CXCR4. In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. In vitro assays showed that PLZF interacts with and inhibits the miR-146a promoter, and that miR-146a targets CXCR4 mRNA, impeding its translation. In megakaryopoietic cultures of CD34+ progenitors, PLZF was upregulated, whereas miR-146a expression decreased and CXCR4 protein increased. MiR-146a overexpression and PLZF or CXCR4 silencing impaired megakaryocytic (Mk) proliferation, differentiation and maturation, as well as Mk colony formation. Mir-146a knockdown induced the opposite effects. Rescue experiments indicated that the effects of PLZF and miR-146a are mediated by miR-146a and CXCR4, respectively. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation.