2. Academic Validation
  3. Optineurin enhances the chemoresistance by activating mitophagy in acute myeloid leukemia with NPM1 mutation

Optineurin enhances the chemoresistance by activating mitophagy in acute myeloid leukemia with NPM1 mutation

  • Free Radic Biol Med. 2026 May:248:162-176. doi: 10.1016/j.freeradbiomed.2026.02.049.
Lisha Tang 1,  Nan Wu 1,  Qiaoling Xiao 2,  Jing Yang 1,  Jun Ren 1,  Xinyi Chen 1,  Wen Zhao 1,  Yongcan Liu 1,  Jiayuan Hu 1,  Zailin Yang 3,  Xiaoling Gao 4,  Ling Zhang 5
Affiliations

Affiliations

  • 1 The Beibei Affiliated Hospital of Chongqing Medical University, The Ninth People's Hospital of Chongqing, Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
  • 2 The Beibei Affiliated Hospital of Chongqing Medical University, The Ninth People's Hospital of Chongqing, Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China; Department of Basic Medicine, Xiamen Medical College, Xiamen, 361023, China.
  • 3 Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China. Electronic address: [email protected].
  • 4 The Beibei Affiliated Hospital of Chongqing Medical University, The Ninth People's Hospital of Chongqing, Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 5 The Beibei Affiliated Hospital of Chongqing Medical University, The Ninth People's Hospital of Chongqing, Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 41722661 DOI: 10.1016/j.freeradbiomed.2026.02.049
Abstract

Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutation is a common genetic subtype with unique pathological features. However, current therapies remain challenged by relapse and drug resistance, underscoring an urgent need for novel therapeutic strategies. In this study, we identified hyperactivated Mitophagy as a critical metabolic vulnerability in NPM1-mutated AML through bioinformatics analysis and experimental validation. Mechanistically, augmented Mitophagy was driven by high expression of the Mitophagy receptor optineurin (OPTN), which was upregulated by cytoplasmic dislocation of CCCTC binding factor (CTCF) in cells harboring the NPM1 mutant. Functionally, OPTN-mediated Mitophagy promoted leukemogenesis by maintaining mitochondrial homeostasis, thereby sustaining leukemia cell proliferation and conferring chemoresistance. Correspondingly, genetic inhibition of OPTN suppressed Mitophagy, disrupted mitochondrial homeostasis, and sensitized cells to cytarabine (Ara-C), ultimately potentiating its antileukemic efficacy in a cell-derived xenograft (CDX) model. Collectively, these findings indicate that OPTN-mediated Mitophagy is an oncogenic driver in NPM1-mutated AML and that, targeted inhibition of this process is a promising strategy for overcoming chemoresistance, particularly in combination with conventional chemotherapy.

Keywords

Acute myeloid leukemia; Chemotherapeutic sensitivity; Mitochondrial homeostasis; Mitophagy; Nucleophosmin 1; OPTN.

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