2. Academic Validation
  3. Oxidative phosphorylation fueled by fatty acid oxidation sensitizes leukemic stem cells to cold

Oxidative phosphorylation fueled by fatty acid oxidation sensitizes leukemic stem cells to cold

  • Cancer Res. 2023 Jun 5;CAN-23-1006. doi: 10.1158/0008-5472.CAN-23-1006.
Emmanuel Griessinger 1,  Diego Pereira-Martins 2,  Marielle Nebout 3,  Claudie Bosc 4,  Estelle Saland 5,  Emeline Boet 6,  Ambrine Sahal 6,  Johanna Chiche 7,  Delphine Debayle 8,  Lucile Fleuriot 9,  Maurien Pruis 1,  Veronique Mansat-De Mas 10,  Francois Vergez 10,  Christian Récher 11,  Gerwin Huls 12,  Jean-Emmanuel Sarry 6,  Jan Jacob Schuringa 2,  Jean-François Peyron 3
Affiliations

Affiliations

  • 1 University Medical Center Groningen, Groningen, Netherlands.
  • 2 UMCG, University of Groningen, Groningen, Netherlands.
  • 3 Université Côte d'Azur, France.
  • 4 Centre de Recherches en Cancérologie de Toulouse, France.
  • 5 INSERM UMR1037, Toulouse, France.
  • 6 Inserm and Universite de Toulouse, Toulouse, France.
  • 7 INSERM U 1065, Nice, France.
  • 8 Université Côte d'Azur, Sophia-Antipolis, France.
  • 9 Université Côte d'Azur, Valbonne, France.
  • 10 Institut Universitaire du Cancer de Toulouse, Toulouse Cedex 9, France.
  • 11 Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, TOULOUSE, France.
  • 12 University Medical Center Groningen, Groningen, Groningen, Netherlands.
PMID: 37272750 DOI: 10.1158/0008-5472.CAN-23-1006
Abstract

Dependency on mitochondrial Oxidative Phosphorylation (OxPhos) is a potential weakness for leukemic stem cells (LSCs) that can be exploited for therapeutic purposes. Fatty acid oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some acute myeloid leukemia (AML) cells, particularly chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge; CKC4), commonly used for sample storage, as a novel vulnerability that selectively kills AML LSCs with active FAO-supported OxPhos while sparing normal hematopoietic stem cells (HSCs). Cell death of OxPhos-positive leukemic cells was induced by membrane permeabilization at 4°C; by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells to activate OxPhos metabolism sensitized them to CKC4. Lipidomic and proteomic analyzes showed that OxPhos shapes the composition of the plasma membrane and introduces variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Together, these findings indicate that steady-state energy metabolism at body temperature predetermines the sensitivity of AML LSCs to cold temperature, suggesting that cold sensitivity could be a potential OxPhos biomarker. These results could have important implications for designing experiments for AML research to avoid cell storage at 4°C.

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