Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling.
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.
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Vincenzo
V
Giambra
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Catherine E
CE
Jenkins
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Sonya H
SH
Lam
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Catherine
C
Hoofd
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Miriam
M
Belmonte
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Xuehai
X
Wang
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Sam
S
Gusscott
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Deanne
D
Gracias
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Andrew P
AP
Weng
D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D014161:Transduction, Genetic; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051176:beta Catenin