Apc regulates the function of hematopoietic stem cells largely through b-catenin–dependent mechanisms

Abstract

Emerging evidence suggests that adenomatous polyposis coli (Apc) plays a critical role in the maintenance of hematopoietic stem/progenitor cells (HSCs/HPCs). The molecular pathways responsible for the function of Apc in HSCs/HPCs remain unclear. By genetic approach, we demonstrated that inactivation of b-catenin rescued the exhaustion of Apc-deficient HSCs/HPCs, thereby preventing bone marrow failure in Apc-deficient mice. b-catenin loss inhibited the excessive proliferation and apoptosis of Apc-deficient HSCs/HPCs, as well as their defects in myeloid and erythroid differentiation. In addition, loss of b-catenin reversed the down-regulation of Cdkn1a, Cdkn1b, and Mcl1 induced by Apc ablation in Lin2Sca1c-Kit1. In assays of long-term stem cell function, the HSCs with deficiency of both Apc and b-catenin displayed a significantly enhanced self-renewal capacity compared with b-catenin–deficient and control HSCs. Our findings suggest that Apc regulates the survival, proliferation, and differentiation of HSCs/HPCs largely through a b-catenin–mediated pathway. They also indicate that multiple downstream targets of Apc including b-catenin may coordinately regulate HSC self-renewal. (Blood. 2013;121(20):4063-4072)