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Chemotherapy resistance in acute myeloid leukemia is mediated by A20 suppression of spontaneous necroptosis

Author

Listed:
  • Ashley E. Culver-Cochran

    (Cincinnati Children’s Hospital)

  • Aishlin Hassan

    (Cincinnati Children’s Hospital)

  • Kathleen Hueneman

    (Cincinnati Children’s Hospital)

  • Kwangmin Choi

    (Cincinnati Children’s Hospital)

  • Averil Ma

    (University of California, San Francisco)

  • Brett VanCauwenbergh

    (Cincinnati Children’s Hospital)

  • Eric O’Brien

    (Cincinnati Children’s Hospital)

  • Mark Wunderlich

    (Cincinnati Children’s Hospital)

  • John P. Perentesis

    (Cincinnati Children’s Hospital
    University of Cincinnati)

  • Daniel T. Starczynowski

    (Cincinnati Children’s Hospital
    University of Cincinnati
    University of Cincinnati
    University of Cincinnati Cancer Center)

Abstract

Acute myeloid leukemia (AML) is a deadly hematopoietic malignancy. Although many patients achieve complete remission with standard induction therapy, a combination of cytarabine and anthracycline, ~40% of patients have induction failure. These refractory patients pose a treatment challenge, as they do not respond to salvage therapy or allogeneic stem cell transplant. Herein, we show that AML patients who experience induction failure have elevated expression of the NF-κB target gene tumor necrosis factor alpha-induced protein-3 (TNFAIP3/A20) and impaired necroptotic cell death. A20High AML are resistant to anthracyclines, while A20Low AML are sensitive. Loss of A20 in AML restores sensitivity to anthracycline treatment by inducing necroptosis. Moreover, A20 prevents necroptosis in AML by targeting the necroptosis effector RIPK1, and anthracycline-induced necroptosis is abrogated in A20High AML. These findings suggest that NF-κB-driven A20 overexpression plays a role in failed chemotherapy induction and highlights the potential of targeting an alternative cell death pathway in AML.

Suggested Citation

  • Ashley E. Culver-Cochran & Aishlin Hassan & Kathleen Hueneman & Kwangmin Choi & Averil Ma & Brett VanCauwenbergh & Eric O’Brien & Mark Wunderlich & John P. Perentesis & Daniel T. Starczynowski, 2024. "Chemotherapy resistance in acute myeloid leukemia is mediated by A20 suppression of spontaneous necroptosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53629-z
    DOI: 10.1038/s41467-024-53629-z
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    References listed on IDEAS

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    1. Motohiro Kato & Masashi Sanada & Itaru Kato & Yasuharu Sato & Junko Takita & Kengo Takeuchi & Akira Niwa & Yuyan Chen & Kumi Nakazaki & Junko Nomoto & Yoshitaka Asakura & Satsuki Muto & Azusa Tamura &, 2009. "Frequent inactivation of A20 in B-cell lymphomas," Nature, Nature, vol. 459(7247), pages 712-716, June.
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