Dose-dependent expression of GFI1 alters metabolism in the haematopoietic progenitors and MLL::AF9-induced leukaemic cells.

Autor:	Patnana PK; Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.; Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, University of Lübeck, Lübeck, Germany., Liu L; Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.; Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China., Frank D; Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.; Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Nimmagadda SC; Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, University of Lübeck, Lübeck, Germany., Behrens M; Institute of Food Chemistry, University of Muenster, Muenster, Germany., Ahmed H; Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, University of Lübeck, Lübeck, Germany., Xie X; Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.; Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China., Liebmann M; Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, Muenster, Germany., Wei L; Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.; Institute of Medical Informatics, University of Muenster, Muenster, Germany., Gerdemann A; Institute of Food Chemistry, University of Muenster, Muenster, Germany., Thivakaran A; Clinic for Pediatrics III, University Hospital Essen, Essen, Germany., Humpf HU; Institute of Food Chemistry, University of Muenster, Muenster, Germany., Klotz L; Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, Muenster, Germany., Dugas M; Institute of Medical Informatics, Heidelberg University Hospital, Heidelberg, Germany., Varghese J; Institute of Medical Informatics, University of Muenster, Muenster, Germany., Trajkovic-Arsic M; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Siveke JT; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Hanenberg H; Clinic for Pediatrics III, University Hospital Essen, Essen, Germany.; Pediatric Oncology, Hematology & Immunology, Heinrich Heine University, University Hospital Düsseldorf, Dusseldorf, Germany., Opalka B; Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Dührsen U; Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Reinhardt HC; Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Guenther U; Institute of Chemistry and Metabolomics, University of Lübeck, Lübeck, Germany., von Bubnoff N; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, University of Lübeck, Lübeck, Germany., Khandanpour C; Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.; Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
Jazyk:	angličtina
Zdroj:	British journal of haematology [Br J Haematol] 2023 Sep; Vol. 202 (5), pp. 1033-1048. Date of Electronic Publication: 2023 Jul 09.
DOI:	10.1111/bjh.18939
Abstrakt:	Growth factor independence 1 (GFI1) is a transcriptional repressor protein that plays an essential role in the differentiation of myeloid and lymphoid progenitors. We and other groups have shown that GFI1 has a dose-dependent role in the initiation, progression, and prognosis of acute myeloid leukaemia (AML) patients by inducing epigenetic changes. We now demonstrate a novel role for dose-dependent GFI1 expression in regulating metabolism in haematopoietic progenitor and leukaemic cells. Using in-vitro and ex-vivo murine models of MLL::AF9-induced human AML and extra-cellular flux assays, we now demonstrate that a lower GFI1 expression enhances oxidative phosphorylation rate via upregulation of the FOXO1- MYC axis. Our findings underscore the significance of therapeutic exploitation in GFI1-low-expressing leukaemia cells by targeting oxidative phosphorylation and glutamine metabolism. (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
Databáze:	MEDLINE
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