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Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response
Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newl...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873558/ https://www.ncbi.nlm.nih.gov/pubmed/36604538 http://dx.doi.org/10.1038/s41591-022-02112-7 |
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author | Lee, Shawn H. R. Yang, Wenjian Gocho, Yoshihiro John, August Rowland, Lauren Smart, Brandon Williams, Hannah Maxwell, Dylan Hunt, Jeremy Yang, Wentao Crews, Kristine R. Roberts, Kathryn G. Jeha, Sima Cheng, Cheng Karol, Seth E. Relling, Mary V. Rosner, Gary L. Inaba, Hiroto Mullighan, Charles G. Pui, Ching-Hon Evans, William E. Yang, Jun J. |
author_facet | Lee, Shawn H. R. Yang, Wenjian Gocho, Yoshihiro John, August Rowland, Lauren Smart, Brandon Williams, Hannah Maxwell, Dylan Hunt, Jeremy Yang, Wentao Crews, Kristine R. Roberts, Kathryn G. Jeha, Sima Cheng, Cheng Karol, Seth E. Relling, Mary V. Rosner, Gary L. Inaba, Hiroto Mullighan, Charles G. Pui, Ching-Hon Evans, William E. Yang, Jun J. |
author_sort | Lee, Shawn H. R. |
collection | PubMed |
description | Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL. We identified six patient clusters based on ALL pharmacotypes, which were associated with event-free survival, even after adjusting for MRD. Pharmacotyping identified a T cell ALL subset with a poor prognosis that was sensitive to targeted agents, pointing to alternative therapeutic strategies. Our study comprehensively described the pharmacological heterogeneity of ALL, highlighting opportunities for further individualizing therapy for this most common childhood cancer. |
format | Online Article Text |
id | pubmed-9873558 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-98735582023-01-26 Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response Lee, Shawn H. R. Yang, Wenjian Gocho, Yoshihiro John, August Rowland, Lauren Smart, Brandon Williams, Hannah Maxwell, Dylan Hunt, Jeremy Yang, Wentao Crews, Kristine R. Roberts, Kathryn G. Jeha, Sima Cheng, Cheng Karol, Seth E. Relling, Mary V. Rosner, Gary L. Inaba, Hiroto Mullighan, Charles G. Pui, Ching-Hon Evans, William E. Yang, Jun J. Nat Med Article Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL. We identified six patient clusters based on ALL pharmacotypes, which were associated with event-free survival, even after adjusting for MRD. Pharmacotyping identified a T cell ALL subset with a poor prognosis that was sensitive to targeted agents, pointing to alternative therapeutic strategies. Our study comprehensively described the pharmacological heterogeneity of ALL, highlighting opportunities for further individualizing therapy for this most common childhood cancer. Nature Publishing Group US 2023-01-05 2023 /pmc/articles/PMC9873558/ /pubmed/36604538 http://dx.doi.org/10.1038/s41591-022-02112-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lee, Shawn H. R. Yang, Wenjian Gocho, Yoshihiro John, August Rowland, Lauren Smart, Brandon Williams, Hannah Maxwell, Dylan Hunt, Jeremy Yang, Wentao Crews, Kristine R. Roberts, Kathryn G. Jeha, Sima Cheng, Cheng Karol, Seth E. Relling, Mary V. Rosner, Gary L. Inaba, Hiroto Mullighan, Charles G. Pui, Ching-Hon Evans, William E. Yang, Jun J. Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response |
title | Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response |
title_full | Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response |
title_fullStr | Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response |
title_full_unstemmed | Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response |
title_short | Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response |
title_sort | pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873558/ https://www.ncbi.nlm.nih.gov/pubmed/36604538 http://dx.doi.org/10.1038/s41591-022-02112-7 |
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