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; Koichi Takahashi

doi:10.1038/s41467-021-22874-x

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 JabbourFarhad Ravandi, Kapil N. Bhalla, Marina Konopleva, Hagop M. Kantarjian, P. Andrew Futreal^*, Koichi Takahashi^*

^*Corresponding author for this work

Surgery, Thoracic Surgery Division

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

79 Scopus citations

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.

Original language	English (US)
Article number	2607
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22874-x
State	Published - Dec 1 2021

Funding

This study was supported in part by the Cancer Prevention Research Institute of Texas (grant R120501 to P.A.F.), the Welch Foundation (grant G-0040 to P.A.F.), the UT System STARS Award (grant PS100149 to P.A.F.), Khalifa Scholar Award (to K.T.), Physician Scientist Program at MD Anderson (to K.T.), V Foundation Lloyd Family Clinical Scholar Award (to C.D.D.), Charif Souki Cancer Research Fund (to H.K.), MD Anderson Cancer Center Leukemia SPORE P50 CA100632 (to H.K.), MD Anderson Cancer Center Support Grant (NIH P30 CA016672), Lynda Hill Foundation (to P.A.F.), JSPS Overseas Research Fellowship (to T.T.), and by generous philanthropic contributions to MD Anderson’s Moon Shot Program for AML/MDS Platform (to H.K., G.G.M., and K.T.). We thank Sunita Patterson at Department Scientific Publications at MD Anderson for providing scientific editing of the manuscript.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Wang, F., Morita, K., DiNardo, C. D., Furudate, K., Tanaka, T., Yan, Y., Patel, K. P., MacBeth, K. J., Wu, B., Liu, G., Frattini, M., Matthews, J. A., Little, L. D., Gumbs, C., Song, X., Zhang, J., Thompson, E. J., Kadia, T. M., Garcia-Manero, G., ... Takahashi, K. (2021). Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia. Nature communications, 12(1), Article 2607. https://doi.org/10.1038/s41467-021-22874-x

@article{98cb96a7d538479f88f51e8da653bda2,

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

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.",

author = "Feng Wang and Kiyomi Morita and DiNardo, {Courtney D.} and Ken Furudate and Tomoyuki Tanaka and Yuanqing Yan and Patel, {Keyur P.} and MacBeth, {Kyle J.} and Bin Wu and Guowen Liu and Mark Frattini and Matthews, {Jairo A.} and Little, {Latasha D.} and Curtis Gumbs and Xingzhi Song and Jianhua Zhang and Thompson, {Erika J.} and Kadia, {Tapan M.} and Guillermo Garcia-Manero and Elias Jabbour and Farhad Ravandi and Bhalla, {Kapil N.} and Marina Konopleva and Kantarjian, {Hagop M.} and {Andrew Futreal}, P. and Koichi Takahashi",

note = "Funding Information: This study was supported in part by the Cancer Prevention Research Institute of Texas (grant R120501 to P.A.F.), the Welch Foundation (grant G-0040 to P.A.F.), the UT System STARS Award (grant PS100149 to P.A.F.), Khalifa Scholar Award (to K.T.), Physician Scientist Program at MD Anderson (to K.T.), V Foundation Lloyd Family Clinical Scholar Award (to C.D.D.), Charif Souki Cancer Research Fund (to H.K.), MD Anderson Cancer Center Leukemia SPORE P50 CA100632 (to H.K.), MD Anderson Cancer Center Support Grant (NIH P30 CA016672), Lynda Hill Foundation (to P.A.F.), JSPS Overseas Research Fellowship (to T.T.), and by generous philanthropic contributions to MD Anderson{\textquoteright}s Moon Shot Program for AML/MDS Platform (to H.K., G.G.M., and K.T.). We thank Sunita Patterson at Department Scientific Publications at MD Anderson for providing scientific editing of the manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-22874-x",

language = "English (US)",

volume = "12",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Wang, F, Morita, K, DiNardo, CD, Furudate, K, Tanaka, T, Yan, Y, Patel, KP, MacBeth, KJ, Wu, B, Liu, G, Frattini, M, Matthews, JA, Little, LD, Gumbs, C, Song, X, Zhang, J, Thompson, EJ, Kadia, TM, Garcia-Manero, G, Jabbour, E, Ravandi, F, Bhalla, KN, Konopleva, M, Kantarjian, HM, Andrew Futreal, P & Takahashi, K 2021, 'Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia', Nature communications, vol. 12, no. 1, 2607. https://doi.org/10.1038/s41467-021-22874-x

TY - JOUR

T1 - Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia

AU - Wang, Feng

AU - Morita, Kiyomi

AU - DiNardo, Courtney D.

AU - Furudate, Ken

AU - Tanaka, Tomoyuki

AU - Yan, Yuanqing

AU - Patel, Keyur P.

AU - MacBeth, Kyle J.

AU - Wu, Bin

AU - Liu, Guowen

AU - Frattini, Mark

AU - Matthews, Jairo A.

AU - Little, Latasha D.

AU - Gumbs, Curtis

AU - Song, Xingzhi

AU - Zhang, Jianhua

AU - Thompson, Erika J.

AU - Kadia, Tapan M.

AU - Garcia-Manero, Guillermo

AU - Jabbour, Elias

AU - Ravandi, Farhad

AU - Bhalla, Kapil N.

AU - Konopleva, Marina

AU - Kantarjian, Hagop M.

AU - Andrew Futreal, P.

AU - Takahashi, Koichi

N1 - Funding Information: This study was supported in part by the Cancer Prevention Research Institute of Texas (grant R120501 to P.A.F.), the Welch Foundation (grant G-0040 to P.A.F.), the UT System STARS Award (grant PS100149 to P.A.F.), Khalifa Scholar Award (to K.T.), Physician Scientist Program at MD Anderson (to K.T.), V Foundation Lloyd Family Clinical Scholar Award (to C.D.D.), Charif Souki Cancer Research Fund (to H.K.), MD Anderson Cancer Center Leukemia SPORE P50 CA100632 (to H.K.), MD Anderson Cancer Center Support Grant (NIH P30 CA016672), Lynda Hill Foundation (to P.A.F.), JSPS Overseas Research Fellowship (to T.T.), and by generous philanthropic contributions to MD Anderson’s Moon Shot Program for AML/MDS Platform (to H.K., G.G.M., and K.T.). We thank Sunita Patterson at Department Scientific Publications at MD Anderson for providing scientific editing of the manuscript. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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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U2 - 10.1038/s41467-021-22874-x

DO - 10.1038/s41467-021-22874-x

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VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2607

ER -

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

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