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.
Pubmed ID: 30991026 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Commercial organization which provides reagents and services for molecular biology research. Its services include clone collections, microRNA solutions, genome editing, qPCR products, and fluorescent labeling and detection.
View all literature mentionsA data repository for proteomic data sets. The ProteomeExchange consortium, as a whole, aims to provide a coordinated submission of MS proteomics data to the main existing proteomics repositories, as well as to encourage optimal data dissemination. ProteomeXchange provides access to a number of public databases, and users can access and submit data sets to the consortium's PRIDE database and PASSEL/PeptideAtlas.
View all literature mentionsWeb application that helps design, evaluate and clone guide sequences for the CRISPR/Cas9 system. This sgRNA design tool assists with guide selection in a variety of genomes and pre-calculated results for all human coding exons as a UCSC Genome Browser track.
View all literature mentionsThis monoclonal targets Phospho-PERK (Thr980)
View all literature mentionsThis polyclonal secondary targets IgG
View all literature mentionsThis monoclonal targets Ubiquitin Lys48-Specific clone Apu2
View all literature mentionsThis unknown targets IgG (H+L)
View all literature mentionsThis unknown targets Phospho-GSK3 alpha/beta (Tyr279, Tyr216)
View all literature mentionsThis monoclonal targets GSK-3alpha/beta
View all literature mentionsThis polyclonal targets Myc-Tag
View all literature mentionsThis recombinant monoclonal targets GAPDH
View all literature mentionsThis unknown targets Non-phospho (Active) β-Catenin (Ser33/37/Thr41) (D13A1) Rabbit mAb
View all literature mentionsThis monoclonal targets β-Catenin
View all literature mentionsThis monoclonal targets p70 S6 Kinase, phospho (Thr389)
View all literature mentions