The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS

Steven W. Lane, Stephen M. Sykes, Fatima Al-Shahrour, Sebastian Shterental, Mahnaz Paktinat, Cristina Lo Celso, Jonathan L. Jesneck, Benjamin L. Ebert, David A. Williams, D. Gary Gilliland

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

Apc, a negative regulator of the canonical Wnt signaling pathway, is a bona-fide tumor suppressor whose loss of function results in intestinal polyposis. APC is located in a commonly deleted region on human chromosome 5q, associated with myelodysplastic syndrome (MDS), suggesting that haploinsufficiency of APC contributes to the MDS phenotype. Analysis of the hematopoietic system of mice with the Apcmin allele that results in a premature stop codon and loss of function showed no abnormality in steady state hematopoiesis. Bone marrow derived from Apcmin mice showed enhanced repopulation potential, indicating a cell intrinsic gain of function in the long-term hematopoietic stem cell (HSC) population. However, Apcmin bone marrow was unable to repopulate secondary recipients because of loss of the quiescent HSC population. Apcmin mice developed a MDS/myeloproliferative phenotype. Our data indicate that Wnt activation through haploinsufficiency of Apc causes insidious loss of HSC function that is only evident in serial transplantation strategies. These data provide a cautionary note for HSC-expansion strategies through Wnt pathway activation, provide evidence that cell extrinsic factors can contribute to the development of myeloid disease, and indicate that loss of function of APC may contribute to the phenotype observed in patients with MDS and del(5q).

Original languageEnglish
Pages (from-to)3489-3497
Number of pages9
JournalBlood
Volume115
Issue number17
DOIs
StatePublished - Apr 29 2010

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