Effects Of Abundance Of β - Catenin Expression On Survival And Function Of Apc - Deficient Hematopoietic Stem Cells

The tumor suppressor gene APC (Adenomatous polyposis coli.) is involved in the initiation and progression of colorectal cancer via regulation of the Wnt signaling cascade. In addition, Apc plays an important role in multiple cellular functions, including cell migration and adhesion, spindle assembly, and chromosome segregation. The role of Apc during adult hematopoiesis is first determined by our lab members.We show that conditional inactivation of Apc in vivo dramatically increases apoptosis and enhances cell cycle entry of hematopoietic stem cells (HSCs)/hematopoietic progenitor cells (HPCs), leading to their rapid disappearance and bone marrow failure. In addition, we found that loss of Apc leads to exhaustion of the myeloid progenitor pool (common myeloid progenitor, granulocyte-monocyte progenitor, and megakaryocyte-erythroid progenitor), as well as the lymphoid-primed multi-potent progenitor pool. Down-regulation of the genes encoding Cdkn1a, Cdknlb, and Mcl1occurs after acute Apc excision in candidate HSC populations. Together, our data previously demonstrated that Apc is essential for HSC and HPC maintenance and survival.The molecular pathways responsible for the function of Apc in HSCs/HPCs still remain unclear. By genetic approaches, we demonstrated that inactivation of β-catenin rescued the exhaustion of Apc-deficient HSCs/HPCs, thereby preventing bone marrow failure in Apc-deficient mice. The Apc-and β-catenin-deficient mice could survive to7months after induction. β-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 β-catenin reversed the down-regulation of Cdknla, Cdkn1b and Mcl1induced by Apc ablation in LSKs. In assays of long-term stem cell function, the HSCs with deficiency of both Apc and β-catenin displayed a significantly enhanced self-renewal capacity compared to β-catenin-deficient and control HSCs. In addition to regulating Wnt/β-catenin signaling, Apc was recently reported to negatively regulate mTOR in293T cells and colorectal carcinoma cells[1,2]. We generated animal models to determine whether loss of Apc also activates the mTOR pathway in hematopoietic cells, thereby contributing to depletion of Apc-deficient HSCs. However, we found that loss of Apc does not activate the mTOR pathway in BM and Lin-cells, and the mTOR inhibitor rapamycin does not prevent Apc-deficient mice from developing bone marrow failure, which indicate that Apc cannot activate the mTOR signaling pathway in hematopoietic cells.Our findings suggest that Apc regulates the survival, proliferation and differentiation of HSCs/HPCs largely through a β-catenin-mediated pathway. They also indicate that multiple down-stream targets of Apc including β-catenin may coordinately regulate HSC self-renewal.