Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias.
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Abstract | 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 GSK3α 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. |
Year of Publication | 2019
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Journal | Cancer Cell
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Volume | 35
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Issue | 4
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Pages | 664-676.e7
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Date Published | 2019 04 15
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ISSN | 1878-3686
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DOI | 10.1016/j.ccell.2019.03.004
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PubMed ID | 30991026
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PubMed Central ID | PMC6541931
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Grant list | R01 CA193651 / CA / NCI NIH HHS / United States
R35 CA210030 / CA / NCI NIH HHS / United States
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