The nonreceptor tyrosine kinase c-Abl phosphorylates Runx1 and regulates Runx1-mediated megakaryocyte maturation

The transcription factor Runx1 is an essential regulator of definitive hematopoiesis, megakaryocyte (MK) maturation, and lymphocyte differentiation. Runx1 mutations that interfere with its transcriptional activity are often present in leukemia patients. Recent work demonstrated that the transcriptional activity of Runx1 is regulated by kinase-mediated phosphorylation. In this study, we showed that c-Abl, but not Arg tyrosine kinase, associated with Runx1 both in cultured cells and in vitro. c-Abl-mediated tyrosine phosphorylation in the Runx1 transcription inhibition domain negatively regulated the transcriptional activity of Runx1 and inhibited Runx1-mediated MK maturation. Consistent with these findings, increased numbers of MKs were detected in the spleens and bone marrow of abl gene conditional knockout mice. Our findings demonstrate an important role of c-Abl kinase in Runx1-mediated MK maturation and platelet formation and provide a potential mechanism of Abl kinase-regulated hematopoiesis.