title: Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block.
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.
authors.affiliation: European Molecular Biology Laboratory Mouse Biology Unit, 00016 Monterotondo, Italy.
authors.forename: Peggy
authors.initials: P
authors.lastname: Kirstetter
authors.forename: Kristina
authors.initials: K
authors.lastname: Anderson
authors.forename: Bo T
authors.initials: BT
authors.lastname: Porse
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D016023:Integrins / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D016023:Integrins; D009687:Nuclear Proteins; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D000099232:Proto-Oncogene Protein Spi-1; C489421:Bmi1 protein, mouse; C493957:Cdkn1a protein, mouse; C513262:Hoxb4 protein, mouse