Open AccessMutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia
Author(s) -
Koichi Oshima,
Junfei Zhao,
Pablo Pérez-Durán,
Jessie Brown,
Juan Ángel Patiño-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. GastierFoster,
Meenakshi Devidas,
Mig 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
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-00124-1
Subject(s) - chemotherapy , drug resistance , disease , leukemia , somatic evolution in cancer , lymphoblastic leukemia , oncology , medicine , biology , gene , cancer research , bioinformatics , genetics
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.