Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia

Oshima K, Zhao J, Pérez-Durán P, Brown JA, Patiño-Galindo JA, Chu T, Quinn A, Gunning T, Belver L, Ambesi-Impiombato A, Tosello V, Wang Z, Sulis ML, Kato M, Koh K, Paganin M, Basso G, Balbin M, Nicolas C, Gastier-Foster JM, Devidas M, Loh ML, Paietta E, Tallman MS, Rowe JM, Litzow M, Minden MD, Meijerink J, Rabadan R, Ferrando A. Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia. Nat Cancer. 2020 Nov;1(11):1113-1127. doi: 10.1038/s43018-020-00124-1. Epub 2020 Oct 19. PubMed PMID: 33796864; PubMed Central PMCID: PMC8011577.

Multi-agent 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 identifies common and drug-specific pathways modulating chemotherapy response and underscores 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 novel therapeutic opportunities for the treatment of relapse and refractory disease.