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

Lane, Steven W., Sykes, Stephen M., Al-Shahrour, Fatima, Shterental, Sebastian, Paktinat, Mahnaz, Lo Celso, Cristina, Jesneck, Jonathan L., Ebert, Benjamin L., Williams, David A. and Gilliland, D. Gary (2010) The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood, 115 17: 3489-3497. doi:10.1182/blood-2009-11-251728


Author Lane, Steven W.
Sykes, Stephen M.
Al-Shahrour, Fatima
Shterental, Sebastian
Paktinat, Mahnaz
Lo Celso, Cristina
Jesneck, Jonathan L.
Ebert, Benjamin L.
Williams, David A.
Gilliland, D. Gary
Title The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS
Formatted title
The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2010-04-29
Sub-type Article (original research)
DOI 10.1182/blood-2009-11-251728
Volume 115
Issue 17
Start page 3489
End page 3497
Total pages 9
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Collection year 2011
Language eng
Formatted 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). © 2010 by The American Society of Hematology.
Keyword Multiple intestinal neoplasia
Gene-expression
Long-term
Self-renewal
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published under Hematopoiesis and Stem Cells

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
 
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Created: Sun, 23 May 2010, 00:06:07 EST