2. Academic Validation
  3. Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia

Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia

  • Leukemia. 2023 Feb 4. doi: 10.1038/s41375-023-01835-x.
Clement Larrue 1 2,  Sarah Mouche # 3 4,  Shan Lin # 5 6,  Federico Simonetta 3 4,  Nastassja K Scheidegger 5 6,  Laury Poulain 3 4,  Rudy Birsen 3 4,  Jean-Emmanuel Sarry 7,  Kimberly Stegmaier 5 6,  Jerome Tamburini 8 9
Affiliations

Affiliations

  • 1 Translational Research Center for Hemato-Oncology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. [email protected].
  • 2 Swiss Cancer Center Leman, Lausanne, Switzerland. [email protected].
  • 3 Translational Research Center for Hemato-Oncology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
  • 4 Swiss Cancer Center Leman, Lausanne, Switzerland.
  • 5 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.
  • 6 The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 7 Cancer Research Centre of Toulouse, UMR1037 Inserm, UMR5077 CNRS, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, 31037, Toulouse, France.
  • 8 Translational Research Center for Hemato-Oncology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. [email protected].
  • 9 Swiss Cancer Center Leman, Lausanne, Switzerland. [email protected].
  • # Contributed equally.
PMID: 36739349 DOI: 10.1038/s41375-023-01835-x
Abstract

Mitochondrial Metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by Dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and Reactive Oxygen Species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.

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