Leukemia stem cells in T-ALL require active Hif1 alpha and Wnt signaling

摘要

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 beta-catenin severely reduces LIC frequency. We show further that beta-catenin transcription is upregulated by hypoxia through hypoxia-inducible factor 1 alpha (Hif1 alpha) stabilization, and that deletion of Hif1a also severely reduces LIC frequency. Of note, the deletion of beta-catenin or Hif1 alpha 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.