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

Koichi Oshima; Junfei Zhao; Pablo Pérez-Durán; Jessie A. Brown; Juan Angel Patiño-Galindo; Timothy Chu; 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 Balbin; Concepcion Nicolas; Julie M. Gastier-Foster; Meenakshi Devidas; Mignon L. Loh; Elisabeth Paietta; Martin S. Tallman; Jacob M. Rowe; Mark Litzow; Mark D. Minden; Jules Meijerink; Raul Rabadan; Adolfo Ferrando

doi:10.1038/s43018-020-00124-1

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

Koichi Oshima, Junfei Zhao, Pablo Pérez-Durán, Jessie A. Brown, Juan Angel Patiño-Galindo, Timothy Chu, 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 Balbin, Concepcion Nicolas, Julie M. Gastier-FosterMeenakshi Devidas, Mignon L. Loh, Elisabeth Paietta, Martin S. Tallman, Jacob M. Rowe, Mark Litzow, Mark D. Minden, Jules Meijerink, Raul Rabadan, Adolfo Ferrando

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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.

Original language	English (US)
Pages (from-to)	1113-1127
Number of pages	15
Journal	Nature Cancer
Volume	1
Issue number	11
DOIs	https://doi.org/10.1038/s43018-020-00124-1
State	Published - Nov 2020

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© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

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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., ... Ferrando, A. (2020). Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia. Nature Cancer, 1(11), 1113-1127. https://doi.org/10.1038/s43018-020-00124-1

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 2020, 'Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia', Nature Cancer, vol. 1, no. 11, pp. 1113-1127. https://doi.org/10.1038/s43018-020-00124-1

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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.",

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doi = "10.1038/s43018-020-00124-1",

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AU - Paietta, Elisabeth

AU - Tallman, Martin S.

AU - Rowe, Jacob M.

AU - Litzow, Mark

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

Abstract

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