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
M3 - Article
C2 - 33972549
AN - SCOPUS:85105602161
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2607
ER -