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

Feng Wang, Kiyomi Morita, Courtney D. DiNardo (), Ken Furudate, Tomoyuki Tanaka, Yuanqing Yan, Keyur P. Patel, Kyle J. MacBeth, Bin Wu, Guowen Liu, Mark Frattini, Jairo A. Matthews, Latasha D. Little, Curtis Gumbs, Xingzhi Song, Jianhua Zhang, Erika J. Thompson, Tapan M. Kadia, Guillermo Garcia-Manero, Elias Jabbour, Farhad Ravandi, Kapil N. Bhalla, Marina Konopleva, Hagop M. Kantarjian, P. Andrew Futreal () and Koichi Takahashi ()
Additional contact information
Feng Wang: The University of Texas MD Anderson Cancer Center
Kiyomi Morita: The University of Texas MD Anderson Cancer Center
Courtney D. DiNardo: The University of Texas MD Anderson Cancer Center
Ken Furudate: The University of Texas MD Anderson Cancer Center
Tomoyuki Tanaka: The University of Texas MD Anderson Cancer Center
Yuanqing Yan: The University of Texas Health Science Center at Houston
Keyur P. Patel: The University of Texas MD Anderson Cancer Center
Kyle J. MacBeth: Celgene Corporation
Bin Wu: Agios Pharmaceuticals
Guowen Liu: Agios Pharmaceuticals
Mark Frattini: Celgene Corporation
Jairo A. Matthews: The University of Texas MD Anderson Cancer Center
Latasha D. Little: The University of Texas MD Anderson Cancer Center
Curtis Gumbs: The University of Texas MD Anderson Cancer Center
Xingzhi Song: The University of Texas MD Anderson Cancer Center
Jianhua Zhang: The University of Texas MD Anderson Cancer Center
Erika J. Thompson: The University of Texas MD Anderson Cancer Center
Tapan M. Kadia: The University of Texas MD Anderson Cancer Center
Guillermo Garcia-Manero: The University of Texas MD Anderson Cancer Center
Elias Jabbour: The University of Texas MD Anderson Cancer Center
Farhad Ravandi: The University of Texas MD Anderson Cancer Center
Kapil N. Bhalla: The University of Texas MD Anderson Cancer Center
Marina Konopleva: The University of Texas MD Anderson Cancer Center
Hagop M. Kantarjian: The University of Texas MD Anderson Cancer Center
P. Andrew Futreal: The University of Texas MD Anderson Cancer Center
Koichi Takahashi: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22874-x

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DOI: 10.1038/s41467-021-22874-x

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