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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
Date Published2019 04 15
KeywordsAnimals, Antineoplastic Agents, Asparaginase, Cell Death, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Glycogen Synthase Kinase 3 beta, Humans, Jurkat Cells, Leukemia, Male, Mice, Inbred NOD, Mice, Transgenic, Polyethylene Glycols, Proteasome Endopeptidase Complex, Protein Kinase Inhibitors, Protein Stability, Proteolysis, Synthetic Lethal Mutations, THP-1 Cells, Ubiquitination, Wnt Signaling Pathway, Wnt3A Protein, Xenograft Model Antitumor Assays

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.


Alternate JournalCancer Cell
PubMed ID30991026
PubMed Central IDPMC6541931
Grant ListR01 CA193651 / CA / NCI NIH HHS / United States
R35 CA210030 / CA / NCI NIH HHS / United States