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

2020; Nature Portfolio; Volume: 1; Issue: 11 Linguagem: Inglês

10.1038/s43018-020-00124-1

2662-1347

Koichi Oshima, Junfei Zhao, Pablo Pérez‐Durán, Jessie Brown, Juan Ángel Patin͂o-Galindo, Timothy Chu, S. Aidan Quinn, Thomas Gunning, Laura Belver, Alberto Ambesi‐Impiombato, Valeria Tosello, Zhengqiang Wang, Maria Luisa Sulis, Motohiro Kato, Katsuyoshi Koh, Maddalena Paganin, Giuseppe Basso, Milagros Balbı́n, Concepción Nicolás, Julie M. Gastier‐Foster, Meenakshi Devidas, Mignon L. Loh, Elisabeth Paietta, Martin S. Tallman, Jacob M. Rowe, Mark R. Litzow, Mark D. Minden, Jules P.P. Meijerink, Raúl Rabadán, Adolfo A. Ferrando,

Cancer therapeutics and mechanisms

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. Ferrando and colleagues analyze matched diagnostic and relapsed acute lymphocytic leukemia by whole-genome sequencing, and perform in vitro genome-wide CRISPR screens, to examine alterations associated with chemotherapy resistance.