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

Author

Listed:
  • 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
    Hirosaki University Graduate School of Medicine)

  • 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
    The University of Texas MD Anderson Cancer Center)

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.

Suggested Citation

  • 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, 2021. "Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22874-x
    DOI: 10.1038/s41467-021-22874-x
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