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Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block

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Author

  • Peggy Kirstetter
  • Kristina Anderson
  • Bo T. Porse
  • Sten Eirik W Jacobsen
  • Claus Nerlov

Summary, in English

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 beta-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 p21(cdk)), 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.

Publishing year

2006

Language

English

Pages

1048-1056

Publication/Series

Nature Immunology

Volume

7

Issue

10

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cell and Molecular Biology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1529-2908