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

Kirstetter, Peggy; Anderson, Kristina LU ; Porse, Bo T.; Jacobsen, Sten Eirik W LU and Nerlov, Claus LU (2006) In Nature Immunology 7(10). p.1048-1056
Abstract
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,... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Immunology
volume
7
issue
10
pages
1048 - 1056
publisher
Nature Publishing Group
external identifiers
  • wos:000241437100010
  • scopus:33748850636
ISSN
1529-2908
DOI
10.1038/ni1381
language
English
LU publication?
yes
id
05179c84-ec77-40f1-b499-5b7bce153086 (old id 386650)
date added to LUP
2007-10-07 15:41:08
date last changed
2019-10-15 05:12:38
@article{05179c84-ec77-40f1-b499-5b7bce153086,
  abstract     = {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.},
  author       = {Kirstetter, Peggy and Anderson, Kristina and Porse, Bo T. and Jacobsen, Sten Eirik W and Nerlov, Claus},
  issn         = {1529-2908},
  language     = {eng},
  number       = {10},
  pages        = {1048--1056},
  publisher    = {Nature Publishing Group},
  series       = {Nature Immunology},
  title        = {Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block},
  url          = {http://dx.doi.org/10.1038/ni1381},
  volume       = {7},
  year         = {2006},
}