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Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are maj...

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Autores principales: Wang, Feng, Morita, Kiyomi, DiNardo, Courtney D., Furudate, Ken, Tanaka, Tomoyuki, Yan, Yuanqing, Patel, Keyur P., MacBeth, Kyle J., Wu, Bin, Liu, Guowen, Frattini, Mark, Matthews, Jairo A., Little, Latasha D., Gumbs, Curtis, Song, Xingzhi, Zhang, Jianhua, Thompson, Erika J., Kadia, Tapan M., Garcia-Manero, Guillermo, Jabbour, Elias, Ravandi, Farhad, Bhalla, Kapil N., Konopleva, Marina, Kantarjian, Hagop M., Andrew Futreal, P., Takahashi, Koichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110775/
https://www.ncbi.nlm.nih.gov/pubmed/33972549
http://dx.doi.org/10.1038/s41467-021-22874-x
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author Wang, Feng
Morita, Kiyomi
DiNardo, Courtney D.
Furudate, Ken
Tanaka, Tomoyuki
Yan, Yuanqing
Patel, Keyur P.
MacBeth, Kyle J.
Wu, Bin
Liu, Guowen
Frattini, Mark
Matthews, Jairo A.
Little, Latasha D.
Gumbs, Curtis
Song, Xingzhi
Zhang, Jianhua
Thompson, Erika J.
Kadia, Tapan M.
Garcia-Manero, Guillermo
Jabbour, Elias
Ravandi, Farhad
Bhalla, Kapil N.
Konopleva, Marina
Kantarjian, Hagop M.
Andrew Futreal, P.
Takahashi, Koichi
author_facet Wang, Feng
Morita, Kiyomi
DiNardo, Courtney D.
Furudate, Ken
Tanaka, Tomoyuki
Yan, Yuanqing
Patel, Keyur P.
MacBeth, Kyle J.
Wu, Bin
Liu, Guowen
Frattini, Mark
Matthews, Jairo A.
Little, Latasha D.
Gumbs, Curtis
Song, Xingzhi
Zhang, Jianhua
Thompson, Erika J.
Kadia, Tapan M.
Garcia-Manero, Guillermo
Jabbour, Elias
Ravandi, Farhad
Bhalla, Kapil N.
Konopleva, Marina
Kantarjian, Hagop M.
Andrew Futreal, P.
Takahashi, Koichi
author_sort Wang, Feng
collection PubMed
description Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.
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spelling pubmed-81107752021-05-14 Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia Wang, Feng Morita, Kiyomi DiNardo, Courtney D. Furudate, Ken Tanaka, Tomoyuki Yan, Yuanqing Patel, Keyur P. MacBeth, Kyle J. Wu, Bin Liu, Guowen Frattini, Mark Matthews, Jairo A. Little, Latasha D. Gumbs, Curtis Song, Xingzhi Zhang, Jianhua Thompson, Erika J. Kadia, Tapan M. Garcia-Manero, Guillermo Jabbour, Elias Ravandi, Farhad Bhalla, Kapil N. Konopleva, Marina Kantarjian, Hagop M. Andrew Futreal, P. Takahashi, Koichi Nat Commun Article Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML. Nature Publishing Group UK 2021-05-10 /pmc/articles/PMC8110775/ /pubmed/33972549 http://dx.doi.org/10.1038/s41467-021-22874-x Text en © The Author(s) 2021 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
Wang, Feng
Morita, Kiyomi
DiNardo, Courtney D.
Furudate, Ken
Tanaka, Tomoyuki
Yan, Yuanqing
Patel, Keyur P.
MacBeth, Kyle J.
Wu, Bin
Liu, Guowen
Frattini, Mark
Matthews, Jairo A.
Little, Latasha D.
Gumbs, Curtis
Song, Xingzhi
Zhang, Jianhua
Thompson, Erika J.
Kadia, Tapan M.
Garcia-Manero, Guillermo
Jabbour, Elias
Ravandi, Farhad
Bhalla, Kapil N.
Konopleva, Marina
Kantarjian, Hagop M.
Andrew Futreal, P.
Takahashi, Koichi
Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
title Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
title_full Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
title_fullStr Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
title_full_unstemmed Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
title_short Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
title_sort leukemia stemness and co-occurring mutations drive resistance to idh inhibitors in acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110775/
https://www.ncbi.nlm.nih.gov/pubmed/33972549
http://dx.doi.org/10.1038/s41467-021-22874-x
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