Nature Immunology
- 7, 1048 - 1056 (2006)
Published online: 3 September 2006; | doi:10.1038/ni1381
Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation blockPeggy Kirstetter1, Kristina Anderson2, Bo T Porse3, Sten Eirik W Jacobsen2 & Claus Nerlov1, 21
European Molecular Biology Laboratory Mouse Biology Unit, 00016 Monterotondo, Italy. 2
Department of Stem Cell Biology, Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, 22184 Lund, Sweden. 3
Laboratory of Gene Therapy Research, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
Correspondence should be addressed to Claus Nerlov nerlov@embl-monterotondo.it
Wnt signaling increases hematopoietic stem cell self-renewal and is activated in both myeloid and lymphoid malignancies, indicating involvement in both normal and malignant hematopoiesis. We report here activated canonical Wnt signaling in the hematopoietic system through conditional expression of a stable form of  -catenin. This enforced expression led to hematopoietic failure associated with loss of myeloid lineage commitment at the granulocyte-macrophage progenitor stage; blocked erythrocyte differentiation; disruption of lymphoid development; and loss of repopulating stem cell activity. Loss of hematopoietic stem cell function was associated with decreased expression of Cdkn1a
(encoding the cell cycle inhibitor p21cdk
), Sfpi1
, Hoxb4
and Bmi1
(encoding the transcription factors PU.1, HoxB4 and Bmi-1, respectively) and altered integrin expression in Lin-Sca-1+c-Kit+ cells, whereas PU.1 was upregulated in erythroid progenitors. Constitutive activation of canonical Wnt signaling therefore causes multilineage differentiation block and compromised hematopoietic stem cell maintenance.
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