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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Uhl, FM; Chen, S; O'Sullivan, D; Edwards-Hicks, J; Richter, G; Haring, E; Andrieux, G; Halbach, S; Apostolova, P; Büscher, J; Duquesne, S; Melchinger, W; Sauer, B; Shoumariyeh, K; Schmitt-Graeff, A; Kreutz, M; Lübbert, M; Duyster, J; Brummer, T; Boerries, M; Madl, T; Blazar, BR; Groß, O; Pearce, EL; Zeiser, R.
Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans.
Sci Transl Med. 2020; 12(567): Doi: 10.1126/scitranslmed.abb8969
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Co-Autor*innen der Med Uni Graz
Madl Tobias
Richter Gesa Lucia

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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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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