The Wnt/β-catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML

By Yingzi Wang, Andrei Krivtsov, Amit U. Sinha, Trista E North, W. Goessling, Zhaohui Feng, Leonard I. Zon, Scott A. Armstrong. Science, 2010

804 citations recorded by the source corpus.

A Pathway to Leukemia Leukemia is initiated and maintained by a small number of self-renewing cells called leukemia stem cells (LSCs), which share properties with hematopoietic stem cells (HSCs), the self-renewing cells that produce healthy blood cells. Wang et al. (p. 1650) studied mouse models of acute myelogenous leukemia (AML), a disease that is often refractory to existing therapies. Activation of the Wnt/β-catenin signaling pathway was required for efficient oncogene-mediated conversion of HSCs into LSCs. This pathway is among the most well studied signaling pathways in cell biology, setting the stage for testing of β-catenin signaling antagonists in preclinical models of AML. The self-renewing cells that drive the growth of leukemia arise, in part, through activation of a well-known cell signaling pathway. Leukemia stem cells (LSCs) are capable of limitless self-renewal and are responsible for the maintenance of leukemia. Because selective eradication of LSCs could offer substantial therapeutic benefit, there is interest in identifying the signaling pathways that control their development. We studied LSCs in mouse models of acute myelogenous leukemia (AML) induced either by coexpression of the Hoxa9 and Meis1a oncogenes or by the fusion oncoprotein MLL-AF9. We show that the Wnt/β-catenin signaling pathway is required for self-renewal of LSCs that are derived from either hematopoietic stem cells (HSC) or more differentiated granulocyte-macrophage progenitors (GMP). Because the Wnt/β-catenin pathway is normally active in HSCs but not in GMP, these results suggest that reactivation of β-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. β-catenin is not absolutely required for self-renewal of adult HSCs; thus, targeting the Wnt/β-catenin pathway may represent a new therapeutic opportunity in AML.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/9454bb26a298b1ac05d45ef99f0d14c3f323c38f

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In Immunology

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In Molecular Biology

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Citations in the corpus

• Wnt signaling in cancer. (2012, background): “In another mouse model of leukemia, initiated by expression of a mixed lineage leukemia (MLL) fusion protein, the conditional ablation of the b-catenin gene prevented preleukemic stem cells from inducing leukemia in grafted animals (Wang et al. 2010).”
• Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “The properties of the cell-of-origin influence the types of mutations that are competent to transform and the properties of the resulting cancer (Huntly et al., 2004; Wang et al., 2010).”
• MLL-rearranged Leukemia is Dependent on Aberrant H3K79 Methylation by DOT1L (2011, neutral): “Generation of Transformed Murine Cells and Leukemia Ecotropic retroviral vectors containing murine MLL-AF9 IRES-GFP, HoxA9IRES-GFP, Meis1a-pgk-Puro, Cre, and MIY were generated by cotransfection of 293 cells. lin or Lin Sca-1+c-Kit+ cells were transduced with MLL-AF9GFP or HoxA9 IRES-GFP andMEIS1a-p”