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Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation

Abstract

Gain of Wnt signaling through β-catenin has been ascribed a critical function in the stimulation of hematopoietic stem cell self-renewal, whereas loss of β-catenin is reportedly dispensable for hematopoiesis. Here we have used conditional mouse genetics and transplantation assays to demonstrate that constitutive activation of β-catenin blocked multilineage differentiation, leading to the death of mice. Blood cell depletion was accompanied by failure of hematopoietic stem cells to repopulate irradiated hosts and to differentiate into mature cells. Activation of β-catenin enforced cell cycle entry of hematopoietic stem cells, thus leading to exhaustion of the long-term stem cell pool. Our data suggest that fine-tuned Wnt stimulation is essential for hematopoiesis and is thus critical for therapeutic hematopoietic stem cell population expansion.

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Figure 1: MxCre-induced β-catenin activation results in rapid lethality.
Figure 2: Activation of β-catenin expands functionally defective HSC populations.
Figure 3: Altered cell cycle and differentiation potential of HSCs expressing activated β-catenin.
Figure 4: Block in erythroid and megakaryocytic differentiation.
Figure 5: Absence of myeloid differentiation.
Figure 6: Myelopoiesis is blocked at the transition from CMP to GMP.
Figure 7: Activated β-catenin arrests lymphoid development.

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Acknowledgements

We thank J. Loehler for histological consultations; J. Lausen, S. Eiglmeier and T. Dayaram for help with real-time RT-PCR; A. Wiener, C. Peter and U. Jahn (Department of Radiotherapy, Robert-Roessle Klinik, Berlin, Germany) for help with animal irradiation experiments; K. Raba and T. Kaiser (Flow cytometry and Cellsorting core facility of Deutsches Rheumaforschungszentrum, Berlin, Germany) for help with sorting of cells. Supported by the Lymphoma Research Foundation (F.R.), the Helmholtz Association (F.R.), the National Center of Competence in Research (J.H.) and the Fondation Leenaards (Lausanne, Switzerland; J.H.).

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All authors contributed to discussions, experimental design, data analysis and the preparation of the manuscript; M.S. designed and executed experiments and prepared the manuscript; J.H. examined the excision of exon 3 in MxCre+Ctnnb1(Ex3)fl/fl mice and the expression of genes downstream of β-catenin and helped to analyze data and to write the manuscript; J.H. and W.B. initiated the collaboration with M.M.T. to analyze the hematopoietic phenotype of Ctnnb1(Ex3)fl/fl mice; F.R. and D.G.T. helped with analyses of HSC gene expression; A.L. supervised the work; and A.L. and M.S. composed the manuscript.

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Correspondence to Achim Leutz.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Experimental schemes. (PDF 80 kb)

Supplementary Fig. 2

Apoptosis and adhesion marker expression in LSK cells. (PDF 81 kb)

Supplementary Table 1

Oligonucleotides used in real-time RT-PCR and genotyping PCR. (PDF 74 kb)

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Scheller, M., Huelsken, J., Rosenbauer, F. et al. Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation. Nat Immunol 7, 1037–1047 (2006). https://doi.org/10.1038/ni1387

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