Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia Journal Article
| Authors: | Oshima, K.; Zhao, J.; Pérez-Durán, P.; Brown, J. A.; Patiño-Galindo, J. A.; Chu, T.; Quinn, A.; Gunning, T.; Belver, L.; Ambesi-Impiombato, A.; Tosello, V.; Wang, Z.; Sulis, M. L.; Kato, M.; Koh, K.; Paganin, M.; Basso, G.; Balbin, M.; Nicolas, C.; Gastier-Foster, J. M.; Devidas, M.; Loh, M. L.; Paietta, E.; Tallman, M. S.; Rowe, J. M.; Litzow, M.; Minden, M. D.; Meijerink, J.; Rabadan, R.; Ferrando, A. |
| Article Title: | Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia |
| Abstract: | 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. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Journal Title: | Nature Cancer |
| Volume: | 1 |
| Issue: | 11 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2020-11-01 |
| Start Page: | 1113 |
| End Page: | 1127 |
| Language: | English |
| DOI: | 10.1038/s43018-020-00124-1 |
| PROVIDER: | scopus |
| PMCID: | PMC8011577 |
| PUBMED: | 33796864 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2020 -- Source: Scopus |
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