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

被引：75

作者：

Wang, Feng ^{[1
]}

Morita, Kiyomi ^{[2
]}

DiNardo, Courtney D. ^{[2
]}

Furudate, Ken ^{[2
,3
]}

Tanaka, Tomoyuki ^{[2
]}

Yan, Yuanqing ^{[4
]}

Patel, Keyur P. ^{[5
]}

MacBeth, Kyle J. ^{[6
]}

Wu, Bin ^{[7
]}

Liu, Guowen ^{[7
]}

Frattini, Mark ^{[6
]}

Matthews, Jairo A. ^{[2
]}

Little, Latasha D. ^{[1
]}

Gumbs, Curtis ^{[1
]}

Song, Xingzhi ^{[1
]}

Zhang, Jianhua ^{[1
]}

Thompson, Erika J. ^{[8
]}

Kadia, Tapan M. ^{[2
]}

Garcia-Manero, Guillermo ^{[2
]}

Jabbour, Elias ^{[2
]}

Ravandi, Farhad ^{[2
]}

Bhalla, Kapil N. ^{[2
]}

Konopleva, Marina ^{[2
]}

Kantarjian, Hagop M. ^{[2
]}

Futreal, P. Andrew ^{[1
]}

Takahashi, Koichi ^{[1
,2
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[3] Hirosaki Univ, Dept Oral & Maxillofacial Surg, Grad Sch Med, Hirosaki, Aomori, Japan

[4] Univ Texas Hlth Sci Ctr Houston, Dept Neurosurg, Houstont, TX USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA

[6] Celgene Corp, Summit, NJ USA

[7] Agios Pharmaceut, Cambridge, MA USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

关键词：

MUTANT IDH2; HYPERMETHYLATION; ENASIDENIB; HISTONE; RISK;

D O I：

10.1038/s41467-021-22874-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The regulation of resistance to IDH inhibitors in acute myeloid leukaemia is not completely understood. Here the authors reveal with integrative multi-omics analyses that stemness features are major drivers of primary resistance, while high-risk mutations drive acquired resistance. 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.

引用

页数：13

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