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

Ashley E. Culver-Cochran, Aishlin Hassan, Kathleen Hueneman, Kwangmin Choi, Averil Ma, Brett VanCauwenbergh, Eric O’Brien, Mark Wunderlich, John P. Perentesis and Daniel T. Starczynowski ()
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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
Daniel T. Starczynowski: Cincinnati Children’s Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53629-z

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