|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Hinze, 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|
|Date Published||2019 Apr 15|
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 Journal||Cancer Cell|