Multiagent combination chemotherapy can be curative in acute lymphoblastic leukemia (ALL). Still, patients with primary refractory disease or with relapsed leukemia have a very poor prognosis. Here we integrate an in-depth dissection of the mutational landscape across diagnostic and relapsed pediatric and adult ALL samples with genome-wide CRISPR screen analysis of gene–drug interactions across seven ALL chemotherapy drugs. By combining these analyses, we uncover diagnostic and relapse-specific mutational mechanisms as well as genetic drivers of chemoresistance. Functionally, our data identify common and drug-specific pathways modulating chemotherapy response and underscore the effect of drug combinations in restricting the selection of resistance-driving genetic lesions. In addition, by identifying actionable targets for the reversal of chemotherapy resistance, these analyses open therapeutic opportunities for the treatment of relapse and refractory disease.
Bibliographical noteFunding Information:
This work was supported by the University of Minnesota Academic Health Center Faculty Research Development Grant (Z.W.); the Leukemia & Lymphoma Society Quest for Cures Award no. 8011-18 (A.F.); an Innovative Research Award and a Phillip A. Sharp Innovation in Collaboration Award by Stand Up to Cancer (A.F.); the St. Baldrick’s Foundation (A.F.); the Chemotherapy Foundation (A.F.); the Swim Across America Foundation (A.F.); a Crazy 8 Pilot Project Award from the Alex Lemonade Stand Foundation (A.F.); the NIH grants no. P30 CA013696 (Genomics and High Throughput Screen Shared Resource, Flow Cytometry Shared Resource, Oncology Precision Therapeutics Shared Resource), no. R35 CA210065 (A.F.), no. R01 CA206501 (A.F.), no. R01 CA185486 (R.R.), no. R01 CA179044 (R.R.), no. U54 CA121852 (R.R.), no. CA180827 (E.P.), no. CA196172 (E.P.), no. CA180820 (ECOG-ACRIN), no. CA189859 (ECOG-ACRIN), no. CA14958 (ECOG-ACRIN), no. CA180791 (ECOG-ACRIN), no. CA17145 (ECOG-ACRIN), no. U10 CA180827 (ECOG-ACRIN), no. CA233332 (ECOG-ACRIN), no. U10 CA180886 (M.L.L.), no. U10 CA98413 (M.L.L.), no. U10 CA180899 (M.L.L.), no. U24 CA114766 (M.L.L.), no. U24-CA196173 (M.L.L.), and no. U10 CA98543 (J.M.G.-F., M.L.L.); the Human Specimen Banking Grant no. U24 CA114766 (J.M.G.-F.); and the Stewart Foundation (R.R.). K.O. is a Rally Foundation fellow. J.A.B. is the Candy and William Raveis Fellow of the Damon Runyon-Sohn Foundation Pediatric Cancer Fellowship Award (grant no. DRSG-31-19).