| Literature DB >> 33796864 |
Koichi Oshima1, Junfei Zhao2,3, Pablo Pérez-Durán1, Jessie A Brown1, Juan Angel Patiño-Galindo2,3, Timothy Chu2,3, Aidan Quinn1, Thomas Gunning1, Laura Belver1, Alberto Ambesi-Impiombato1,4, Valeria Tosello5, Zhengqiang Wang6, Maria Luisa Sulis7, Motohiro Kato8, Katsuyoshi Koh8, Maddalena Paganin9,10, Giuseppe Basso10,11, Milagros Balbin12,13, Concepcion Nicolas14, Julie M Gastier-Foster15,16,17, Meenakshi Devidas18,19, Mignon L Loh20,21, Elisabeth Paietta22, Martin S Tallman23, Jacob M Rowe24, Mark Litzow25, Mark D Minden26, Jules Meijerink27, Raul Rabadan28,29, Adolfo Ferrando30,31,32,33.
Abstract
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.Entities:
Mesh：
Year: 2020 PMID： 33796864 PMCID： PMC8011577 DOI： 10.1038/s43018-020-00124-1
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347