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

Center for Drug Design

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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

Bibliographical note

Funding Information:
This work was supported by the University of Minnesota Academic Health Center Faculty Research Development Grant (Z.W.); the Leukemia & Lymphoma Society Quest for Cures Award no. 8011-18 (A.F.); an Innovative Research Award and a Phillip A. Sharp Innovation in Collaboration Award by Stand Up to Cancer (A.F.); the St. Baldrick’s Foundation (A.F.); the Chemotherapy Foundation (A.F.); the Swim Across America Foundation (A.F.); a Crazy 8 Pilot Project Award from the Alex Lemonade Stand Foundation (A.F.); the NIH grants no. P30 CA013696 (Genomics and High Throughput Screen Shared Resource, Flow Cytometry Shared Resource, Oncology Precision Therapeutics Shared Resource), no. R35 CA210065 (A.F.), no. R01 CA206501 (A.F.), no. R01 CA185486 (R.R.), no. R01 CA179044 (R.R.), no. U54 CA121852 (R.R.), no. CA180827 (E.P.), no. CA196172 (E.P.), no. CA180820 (ECOG-ACRIN), no. CA189859 (ECOG-ACRIN), no. CA14958 (ECOG-ACRIN), no. CA180791 (ECOG-ACRIN), no. CA17145 (ECOG-ACRIN), no. U10 CA180827 (ECOG-ACRIN), no. CA233332 (ECOG-ACRIN), no. U10 CA180886 (M.L.L.), no. U10 CA98413 (M.L.L.), no. U10 CA180899 (M.L.L.), no. U24 CA114766 (M.L.L.), no. U24-CA196173 (M.L.L.), and no. U10 CA98543 (J.M.G.-F., M.L.L.); the Human Specimen Banking Grant no. U24 CA114766 (J.M.G.-F.); and the Stewart Foundation (R.R.). K.O. is a Rally Foundation fellow. J.A.B. is the Candy and William Raveis Fellow of the Damon Runyon-Sohn Foundation Pediatric Cancer Fellowship Award (grant no. DRSG-31-19).

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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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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.",

author = "Koichi Oshima and Junfei Zhao and Pablo P{\'e}rez-Dur{\'a}n and Brown, {Jessie A.} and Pati{\~n}o-Galindo, {Juan Angel} and Timothy Chu and Aidan Quinn and Thomas Gunning and Laura Belver and Alberto Ambesi-Impiombato and Valeria Tosello and Zhengqiang Wang and Sulis, {Maria Luisa} and Motohiro Kato and Katsuyoshi Koh and Maddalena Paganin and Giuseppe Basso and Milagros Balbin and Concepcion Nicolas and Gastier-Foster, {Julie M.} and Meenakshi Devidas and Loh, {Mignon L.} and Elisabeth Paietta and Tallman, {Martin S.} and Rowe, {Jacob M.} and Mark Litzow and Minden, {Mark D.} and Jules Meijerink and Raul Rabadan and Adolfo Ferrando",

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

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T1 - Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia

AU - Oshima, Koichi

AU - Zhao, Junfei

AU - Pérez-Durán, Pablo

AU - Brown, Jessie A.

AU - Patiño-Galindo, Juan Angel

AU - Chu, Timothy

AU - Quinn, Aidan

AU - Gunning, Thomas

AU - Belver, Laura

AU - Ambesi-Impiombato, Alberto

AU - Tosello, Valeria

AU - Wang, Zhengqiang

AU - Sulis, Maria Luisa

AU - Kato, Motohiro

AU - Koh, Katsuyoshi

AU - Paganin, Maddalena

AU - Basso, Giuseppe

AU - Balbin, Milagros

AU - Nicolas, Concepcion

AU - Gastier-Foster, Julie M.

AU - Devidas, Meenakshi

AU - Loh, Mignon L.

AU - Paietta, Elisabeth

AU - Tallman, Martin S.

AU - Rowe, Jacob M.

AU - Litzow, Mark

AU - Minden, Mark D.

AU - Meijerink, Jules

AU - Rabadan, Raul

AU - Ferrando, Adolfo

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N2 - 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.

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

Abstract

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