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

TY - JOUR

T1 - Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block.

AU - Kirstetter, Peggy

AU - Anderson, Kristina

AU - Porse, Bo T

AU - Jacobsen, Sten Eirik W

AU - Nerlov, Claus

N1 - Keywords: Animals; Cell Differentiation; Cell Lineage; Cyclin-Dependent Kinase Inhibitor p21; Gene Expression; Gene Expression Regulation; Hematopoiesis; Hematopoietic Stem Cells; Homeodomain Proteins; Integrins; Mice; Mice, Mutant Strains; Nuclear Proteins; Proto-Oncogene Proteins; Repressor Proteins; Signal Transduction; Trans-Activators; Transcription Factors; Wnt Proteins; beta Catenin

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1038/ni1381

DO - 10.1038/ni1381

M3 - Journal article

C2 - 16951689

SN - 1529-2908

VL - 7

SP - 1048

EP - 1056

JO - Nature Immunology

JF - Nature Immunology

IS - 10

ER -