PMID- 37272750
OWN - NLM
STAT- MEDLINE
DCOM- 20230802
LR  - 20230803
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 83
IP  - 15
DP  - 2023 Aug 1
TI  - Oxidative Phosphorylation Fueled by Fatty Acid Oxidation Sensitizes Leukemic Stem 
      Cells to Cold.
PG  - 2461-2470
LID - 10.1158/0008-5472.CAN-23-1006 [doi]
AB  - Dependency on mitochondrial oxidative phosphorylation (OxPhos) is a potential 
      weakness for leukemic stem cells (LSC) 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 degrees 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. Cell death of OxPhos-positive 
      leukemic cells was induced by membrane permeabilization at 4 degrees 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 analyses 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 degrees C. SIGNIFICANCE: 
      Mitochondrial metabolism fueled by FAO alters the membrane composition and 
      introduces membrane fragility upon cold exposure in OxPhos-driven AML and in 
      LSCs. See related commentary by Jones, p. 2441.
CI  - (c)2023 The Authors; Published by the American Association for Cancer Research.
FAU - Griessinger, Emmanuel
AU  - Griessinger E
AUID- ORCID: 0000-0001-7529-4187
AD  - Department of Experimental Hematology, University Medical Center Groningen, 
      University of Groningen, Groningen, the Netherlands.
AD  - Universite Cote d'Azur, INSERM, U1065, Centre Mediterraneen de Medecine 
      Moleculaire (C3M), Nice, France.
FAU - Pereira-Martins, Diego
AU  - Pereira-Martins D
AUID- ORCID: 0000-0002-3302-4311
AD  - Department of Experimental Hematology, University Medical Center Groningen, 
      University of Groningen, Groningen, the Netherlands.
FAU - Nebout, Marielle
AU  - Nebout M
AUID- ORCID: 0009-0004-7173-3794
AD  - Universite Cote d'Azur, INSERM, U1065, Centre Mediterraneen de Medecine 
      Moleculaire (C3M), Nice, France.
FAU - Bosc, Claudie
AU  - Bosc C
AUID- ORCID: 0000-0003-1435-3475
AD  - Centre de Recherches en Cancerologie de Toulouse, Universite de Toulouse, 
      Institut National de la Sante et de la Recherche Medicale, Centre National de la 
      Recherche Scientifique, Toulouse, France.
AD  - LabEx Toucan, Toulouse, France.
AD  - Equipe Labellisee Ligue Nationale Contre le Cancer 2018, Toulouse, France.
FAU - Saland, Estelle
AU  - Saland E
AUID- ORCID: 0000-0001-8521-3061
AD  - Centre de Recherches en Cancerologie de Toulouse, Universite de Toulouse, 
      Institut National de la Sante et de la Recherche Medicale, Centre National de la 
      Recherche Scientifique, Toulouse, France.
AD  - LabEx Toucan, Toulouse, France.
AD  - Equipe Labellisee Ligue Nationale Contre le Cancer 2018, Toulouse, France.
FAU - Boet, Emiline
AU  - Boet E
AUID- ORCID: 0000-0002-7718-8692
AD  - Centre de Recherches en Cancerologie de Toulouse, Universite de Toulouse, 
      Institut National de la Sante et de la Recherche Medicale, Centre National de la 
      Recherche Scientifique, Toulouse, France.
AD  - LabEx Toucan, Toulouse, France.
AD  - Equipe Labellisee Ligue Nationale Contre le Cancer 2018, Toulouse, France.
FAU - Sahal, Ambrine
AU  - Sahal A
AUID- ORCID: 0000-0003-4755-2884
AD  - Centre de Recherches en Cancerologie de Toulouse, Universite de Toulouse, 
      Institut National de la Sante et de la Recherche Medicale, Centre National de la 
      Recherche Scientifique, Toulouse, France.
AD  - LabEx Toucan, Toulouse, France.
AD  - Equipe Labellisee Ligue Nationale Contre le Cancer 2018, Toulouse, France.
FAU - Chiche, Johanna
AU  - Chiche J
AUID- ORCID: 0000-0001-5276-1125
AD  - Universite Cote d'Azur, INSERM, U1065, Centre Mediterraneen de Medecine 
      Moleculaire (C3M), Nice, France.
AD  - Equipe labellisee Ligue Contre le Cancer, Nice, France.
FAU - Debayle, Delphine
AU  - Debayle D
AUID- ORCID: 0000-0003-2807-9198
AD  - Universite Cote d'Azur, CNRS, IPMC, Valbonne, France.
FAU - Fleuriot, Lucile
AU  - Fleuriot L
AUID- ORCID: 0000-0001-9452-8188
AD  - Universite Cote d'Azur, CNRS, IPMC, Valbonne, France.
FAU - Pruis, Maurien
AU  - Pruis M
AUID- ORCID: 0009-0007-5212-0636
AD  - Department of Experimental Hematology, University Medical Center Groningen, 
      University of Groningen, Groningen, the Netherlands.
FAU - De Mas, Veronique
AU  - De Mas V
AUID- ORCID: 0000-0003-1878-9129
AD  - Service d'Hematologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU 
      de Toulouse, Toulouse, France.
FAU - Vergez, Francois
AU  - Vergez F
AUID- ORCID: 0000-0002-0063-4404
AD  - Service d'Hematologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU 
      de Toulouse, Toulouse, France.
FAU - Recher, Christian
AU  - Recher C
AUID- ORCID: 0000-0002-3332-4525
AD  - Service d'Hematologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU 
      de Toulouse, Toulouse, France.
FAU - Huls, Gerwin
AU  - Huls G
AUID- ORCID: 0009-0001-6789-6433
AD  - Department of Experimental Hematology, University Medical Center Groningen, 
      University of Groningen, Groningen, the Netherlands.
FAU - Sarry, Jean-Emmanuel
AU  - Sarry JE
AUID- ORCID: 0000-0002-6704-2032
AD  - Centre de Recherches en Cancerologie de Toulouse, Universite de Toulouse, 
      Institut National de la Sante et de la Recherche Medicale, Centre National de la 
      Recherche Scientifique, Toulouse, France.
AD  - LabEx Toucan, Toulouse, France.
AD  - Equipe Labellisee Ligue Nationale Contre le Cancer 2018, Toulouse, France.
FAU - Schuringa, Jan Jacob
AU  - Schuringa JJ
AUID- ORCID: 0000-0001-8452-8555
AD  - Department of Experimental Hematology, University Medical Center Groningen, 
      University of Groningen, Groningen, the Netherlands.
FAU - Peyron, Jean-Francois
AU  - Peyron JF
AUID- ORCID: 0000-0001-6113-916X
AD  - Universite Cote d'Azur, INSERM, U1065, Centre Mediterraneen de Medecine 
      Moleculaire (C3M), Nice, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Fatty Acids)
SB  - IM
CIN - Cancer Res. 2023 Aug 1;83(15):2441-2442. PMID: 37525977
MH  - Humans
MH  - *Oxidative Phosphorylation
MH  - Cold Temperature
MH  - Proteomics
MH  - *Leukemia, Myeloid, Acute/drug therapy
MH  - Hematopoietic Stem Cells/metabolism
MH  - Fatty Acids/metabolism
MH  - Neoplastic Stem Cells/metabolism
PMC - PMC10391327
EDAT- 2023/06/05 13:04
MHDA- 2023/08/02 06:42
PMCR- 2023/08/01
CRDT- 2023/06/05 09:33
PHST- 2023/04/17 00:00 [received]
PHST- 2023/05/24 00:00 [revised]
PHST- 2023/05/31 00:00 [accepted]
PHST- 2023/08/02 06:42 [medline]
PHST- 2023/06/05 13:04 [pubmed]
PHST- 2023/06/05 09:33 [entrez]
PHST- 2023/08/01 00:00 [pmc-release]
AID - 727162 [pii]
AID - CAN-23-1006 [pii]
AID - 10.1158/0008-5472.CAN-23-1006 [doi]
PST - ppublish
SO  - Cancer Res. 2023 Aug 1;83(15):2461-2470. doi: 10.1158/0008-5472.CAN-23-1006.