C-Myb Controls Hematopoietic Stem Cell Quiescence and Differentiation Via Regulation of p57^Kip2

Abstract 3878

A seminal feature of long-term hematopoietic stem cells (HSC) is quiescence. We recently described a mutation of the transcription factor c-Myb, M303V that leads to thrombocytosis and a ten-fold increase HSC number. Here we report that increased HSC number in c-Myb^M303V mice results from increased cycling of long-term and short-term HSC. Analysis of cell cycle genes revealed a decrease in the cell cycle inhibitor p57^kip2 (Cdkn1c), a gene expressed in long-term but not short-term HSC. Mechanistic studies reveal that c-Myb binds and activates the p57 promoter and this capacity is diminished by the c-Myb^M303V mutation. Restoration of p57 in c-Myb^M303V HSC prevents thrombocytosis and shRNA mediated reduction of p57 in HSC followed by transplantation leads to enhanced numbers of HSC. These data highlight c-Myb and p57 as key regulators of HSC quiescence and differentiation.