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Oshima K, Zhao J, Pérez-Durán P, et al. Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia. Nat Cancer. 2020;1(11):1113-1127doi: 10.1038/s43018-020-00124-1.
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. (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, Koichi, et al. "Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia." Nature cancer vol. 1,11 (2020): 1113-1127. doi: 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. Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia. Nat Cancer. 2020 Nov;1(11):1113-1127. doi: 10.1038/s43018-020-00124-1. Epub 2020 Oct 19. PMID: 33796864; PMCID: PMC8011577.
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Nat Cancer. 2020 Nov;1(11):1113-1127. doi: 10.1038/s43018-020-00124-1. Epub 2020 Oct 19.

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

Nature cancer

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

Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, NY, USA.
  2. These authors contributed equally: Koichi Oshima, Junfei Zhao, Pablo Pérez-Durán, Jessie A. Brown.
  3. Department of Systems Biology, Columbia University, New York, NY, USA.
  4. Department of Biomedical Informatics, Columbia University, New York, NY, USA.
  5. Present address: PsychoGenics, Paramus, NJ, USA.
  6. Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  7. Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
  8. Department of Pediatric Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  9. Department of Hematology-Oncology, Saitama Children's Medical Center, Saitama, Japan.
  10. Fondazione Città della Speranza, Istituto di Ricerca Pediatrica, Padova, Italy.
  11. Haematology-Oncology Division, Department of Woman's and Child's Health, University Hospital of Padua, Padua, Italy.
  12. Present address: IIGM Italian Institute of Genomic Medicine, Turin, Italy.
  13. Molecular Oncology Laboratory, Instituto Universitario de Oncologia del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
  14. Instituto de Investigación Sanitaria del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
  15. Hematology Service, Hospital Universitario Central de Asturias, Oviedo, Spain.
  16. Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
  17. Departments of Pathology and Pediatrics, Ohio State University School of Medicine, Columbus, OH, USA.
  18. Children's Oncology Group, Arcadia, CA, USA.
  19. Department of Biostatistics, University of Florida, Gainesville, FL, USA.
  20. Present address: Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA.
  21. Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
  22. Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
  23. Montefiore Medical Center, Bronx, NY, USA.
  24. Department of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  25. Shaare Zedek Medical Center, Jerusalem, Israel.
  26. Mayo Clinic, Rochester, MN, USA.
  27. Department of Oncology/Hematology, Princess Margaret Cancer Center, Toronto, ON, Canada.
  28. Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  29. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
  30. Department of Pediatrics, Columbia University, New York, NY, USA.

PMID: 33796864 PMCID: PMC8011577 DOI: 10.1038/s43018-020-00124-1

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.

Conflict of interest statement

Competing financial interests The authors declare no competing financial interests relevant for the work reported here. Financial disclosures for Adolfo Ferrando: Consulting for Ayala Pharmaceuticals

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