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Targeting mitochondrial TRIP13-AIF interaction suppresses myeloid leukemia progression and overcomes drug resistance

Yao Zhu1, Hongcai Liu1, Fuqiang Wang1

  • 1State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China.

Oncogene
|June 13, 2026
PubMed

Insights

Researchers identified the ATPase TRIP13 as a key driver in acute myeloid leukemia (AML) progression and venetoclax resistance. Targeting the TRIP13-AIF interaction offers a promising new therapeutic strategy for AML patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Venetoclax-based therapies have transformed acute myeloid leukemia (AML) treatment.
  • Disease progression and drug resistance remain significant challenges in AML therapy.
  • Cancer-Testis (CT) genes, aberrantly activated in cancer, represent potential therapeutic targets.

Purpose of the Study:

  • To identify novel molecular drivers of AML progression and resistance.
  • To investigate the role of CT genes and CT-like genes in AML.
  • To explore the therapeutic potential of targeting identified pathways.

Main Methods:

  • Conducted a CRISPR screen focusing on CT genes and CT-like genes.
  • Utilized genetic mouse models to assess gene function in AML and normal hematopoiesis.
  • Investigated the molecular mechanism of TRIP13 in leukemia cells, including its interaction with AIF and localization.
  • Assessed the impact of disrupting the TRIP13-AIF interaction on cellular viability, metabolism, and drug resistance in vitro and in vivo.

Main Results:

  • Identified the ATPase TRIP13 as essential for AML progression but not normal hematopoiesis.
  • Discovered that TRIP13 localizes to mitochondria and interacts with AIF, a component of respiratory complex I.
  • This interaction prevents AIF nuclear translocation, reduces apoptosis, and promotes oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO).
  • Disrupting the TRIP13-AIF interaction inhibited OXPHOS, decreased leukemia cell viability, and overcame venetoclax resistance in preclinical models.

Conclusions:

  • AML cells exploit germline programs, like CT gene activation, to sustain progression and resist therapy.
  • The TRIP13-AIF interaction is a novel mechanism driving AML progression and drug resistance.
  • Targeting the TRIP13-AIF interaction presents a promising therapeutic strategy for overcoming venetoclax resistance in AML.

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