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.