Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling
| Autor: | Miriam Belmonte, Vincenzo Giambra, Catherine Hoofd, Xuehai Wang, Catherine E. Jenkins, Sam Gusscott, Sonya H Lam, Deanne Gracias, Andrew P. Weng |
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| Rok vydání: | 2014 |
| Předmět: |
Chromatin Immunoprecipitation
Beta-catenin Immunology Mice Transgenic Biology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Biochemistry Polymerase Chain Reaction Mice Cancer stem cell Transduction Genetic Cell Line Tumor medicine Animals Humans Wnt Signaling Pathway beta Catenin Lymphoid Neoplasia Wnt signaling pathway Hematopoietic stem cell LRP5 Cell Biology Hematology medicine.disease Flow Cytometry Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Mice Inbred C57BL Leukemia medicine.anatomical_structure biology.protein Cancer research Neoplastic Stem Cells Heterografts Stem cell Chronic myelogenous leukemia |
| Zdroj: | Blood. 125(25) |
| ISSN: | 1528-0020 |
| Popis: | The Wnt signaling pathway has been shown to play important roles in normal hematopoietic stem cell biology and in the development of both acute and chronic myelogenous leukemia. Its role in maintaining established leukemia stem cells, which are more directly relevant to patients with disease, however, is less clear. To address what role Wnt signaling may play in T-cell acute lymphoblastic leukemia (T-ALL), we used a stably integrated fluorescent Wnt reporter construct to interrogate endogenous Wnt signaling activity in vivo. In this study, we report that active Wnt signaling is restricted to minor subpopulations within bulk tumors, that these Wnt-active subsets are highly enriched for leukemia-initiating cells (LICs), and that genetic inactivation of β-catenin severely reduces LIC frequency. We show further that β-catenin transcription is upregulated by hypoxia through hypoxia-inducible factor 1α (Hif1α) stabilization, and that deletion of Hif1α also severely reduces LIC frequency. Of note, the deletion of β-catenin or Hif1α did not impair the growth or viability of bulk tumor cells, suggesting that elements of the Wnt and Hif pathways specifically support leukemia stem cells. We also confirm the relevance of these findings to human disease using cell lines and patient-derived xenografts, suggesting that targeting these pathways could benefit patients with T-ALL. |
| Databáze: | OpenAIRE |
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