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Cancer Cell DOI:10.1016/j.ccell.2019.03.004

Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias.

Publication TypeJournal Article
Year of Publication2019
AuthorsHinze, L, Pfirrmann, M, Karim, S, Degar, J, McGuckin, C, Vinjamur, D, Sacher, J, Stevenson, KE, Neuberg, DS, Orellana, E, Stanulla, M, Gregory, RI, Bauer, DE, Wagner, FF, Stegmaier, K, Gutierrez, A
JournalCancer Cell
Volume35
Issue4
Pages664-676.e7
Date Published2019 Apr 15
ISSN1878-3686
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.

DOI10.1016/j.ccell.2019.03.004
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30991026?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID30991026