A critical role for Apc in hematopoietic stem and progenitor cell survival.
The adenomatous polyposis coli (Apc) tumor suppressor 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. However, its role during adult hematopoiesis is unknown. 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. The defect in HSCs/HPCs caused by Apc ablation is cell autonomous. 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 multipotent progenitor pool. Down-regulation of the genes encoding Cdkn1a, Cdkn1b, and Mcl1 occurs after acute Apc excision in candidate HSC populations. Together, our data demonstrate that Apc is essential for HSC and HPC maintenance and survival.
Qian
Zhijian
Z
Section of Hematology/Oncology and the Cancer Research Center, University of Chicago, Chicago, IL 60637, USA. zqian@bsd.uchicago.edu
Chen
Lina
L
Fernald
Anthony A
AA
Williams
Bart O
BO
Le Beau
Michelle M
MM
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002470:Cell Survival; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology; D013234:Stem Cells / Q000166:cytology*
D025601:Adenomatous Polyposis Coli Protein