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  Metabolic reprogramming of donor T cells enhances graf-versus-leukemia effects in mice and humans

Uhl, F. M., Chen, S., O'Sullivan, D., Edwards-Hicks, J., Richter, G., Haring, E., et al. (2020). Metabolic reprogramming of donor T cells enhances graf-versus-leukemia effects in mice and humans. Science translational medicine: integrating medicine and science / American Association for the Advancement of Science, 12, eabb8969. doi:10.1126/scitranslmed.abb8969.

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Uhl et al. 2020.pdf (Publisher version), 10MB
 
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 Creators:
Uhl, Franziska M.1, Author
Chen, Sophia1, Author
O'Sullivan, David2, Author              
Edwards-Hicks, Joy2, Author
Richter, Gesa1, Author
Haring, Eileen1, Author
Andrieux, Geoffroy1, Author
Halbach, Sebastian1, Author
Apostalova, Petya2, Author
Büscher, Jörg Martin2, Author              
Duquesne, Sandra1, Author
Melchinger, Wolfgang1, Author
Sauer, Barbara1, Author
Shoumariyeh, Khalid1, Author
Schmitt-Graeff, Annette1, Author
Kreutz, Marina1, Author
Lübbert, Michael1, Author
Duyster, Justus1, Author
Brummer, Tilman1, Author
Boerries, Melanie1, Author
Madl, Tobias1, AuthorBlazar, Bruce R.1, AuthorGroß, Olaf1, AuthorPearce, Erika L.2, Author              Zeiser, Robert1, Author more..
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1External Organizations, ou_persistent22              
2Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243648              

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 Abstract: Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis. We found that T cells of patients relapsing with AML after allo-HCT exhibited reduced glycolysis and interferon-γ production. Functional studies in multiple mouse models of leukemia showed that leukemia-derived lactic acid (LA) interfered with T cell glycolysis and proliferation. Mechanistically, LA reduced intracellular pH in T cells, led to lower transcription of glycolysis-related enzymes, and decreased activity of essential metabolic pathways. Metabolic reprogramming by sodium bicarbonate (NaBi) reversed the LA-induced low intracellular pH, restored metabolite concentrations, led to incorporation of LA into the tricarboxylic acid cycle as an additional energy source, and enhanced graft-versus-leukemia activity of murine and human T cells. NaBi treatment of post–allo-HCT patients with relapsed AML improved metabolic fitness and interferon-γ production in T cells. Overall, we show that metabolic reprogramming of donor T cells is a pharmacological strategy for patients with relapsed AML after allo-HCT.

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Language(s): eng - English
 Dates: 2020-10-28
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1126/scitranslmed.abb8969
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Title: Science translational medicine : integrating medicine and science / American Association for the Advancement of Science
  Other : Science translational medicine
  Abbreviation : Sci Transl Med
Source Genre: Journal
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Publ. Info: Washington, DC, USA : American Association for the Advancement of Science
Pages: - Volume / Issue: 12 Sequence Number: - Start / End Page: eabb8969 Identifier: ISSN: 1946-6242
CoNE: https://pure.mpg.de/cone/journals/resource/1946-6242