期刊
CANCER CELL
卷 35, 期 4, 页码 664-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2019.03.004
关键词
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资金
- NIH/NCI [1R01CA193651, R35 CA210030]
- Boston Children's Hospital Translational Investigator Service
- Victoria Ann Schuerch Memorial Foundation and Victoria's Walk
- German National Academic Foundation
- Biomedical Education Program
- CHPA Investigatorship at Boston Children's Hospital
- Leukemia and Lymphoma Society Scholar Award
Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits glycogen synthase kinase 3 (GSK3)-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3 alpha inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase.
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