期刊
BLOOD
卷 121, 期 20, 页码 4063-4072出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-12-473470
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资金
- National Institutes of Health Cancer Institute [RO1 CA140979]
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 beta-catenin rescued the exhaustion of Apc-deficient HSCs/HPCs, thereby preventing bone marrow failure in Apc-deficient mice. beta-catenin loss inhibited the excessive proliferation and apoptosis of Apcdeficient HSCs/HPCs, as well as their defects in myeloid and erythroid differentiation. In addition, loss of beta-catenin reversed the down-regulation of Cdkn1a, Cdkn1b, and Mcl1 induced by Apc ablation in Lin(-)Sca(+)c-Kit(+). In assays of long-term stem cell function, the HSCs with deficiency of both Apc and beta-catenin displayed a significantly enhanced self-renewal capacity compared with beta-catenin-deficient and control HSCs. Our findings suggest that Apc regulates the survival, proliferation, and differentiation of HSCs/HPCs largely through a beta-catenin-mediated pathway. They also indicate that multiple downstream targets of Apc including beta-catenin may coordinately regulate HSC self-renewal.
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