GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2022-07-08

AUTHORS

Longlong Liu, Pradeep Kumar Patnana, Xiaoqing Xie, Daria Frank, Subbaiah Chary Nimmagadda, Minhua Su, Donghua Zhang, Thorsten Koenig, Frank Rosenbauer, Marie Liebmann, Luisa Klotz, Wendan Xu, Jan Vorwerk, Felix Neumann, Jana Hüve, Andreas Unger, Jürgen Günther Okun, Bertram Opalka, Cyrus Khandanpour

ABSTRACT

Recent studies highlighted the role of transcription factors in metabolic regulation during hematopoiesis and leukemia development. GFI1B is a transcriptional repressor that plays a critical role in hematopoiesis, and its expression is negatively related to the prognosis of acute myeloid leukemia (AML) patients. We earlier reported a change in the metabolic state of hematopoietic stem cells upon Gfi1b deletion. Here we explored the role of Gfi1b in metabolism reprogramming during hematopoiesis and leukemogenesis. We demonstrated that Gfi1b deletion remarkably activated mitochondrial respiration and altered energy metabolism dependence toward oxidative phosphorylation (OXPHOS). Mitochondrial substrate dependency was shifted from glucose to fatty acids upon Gfi1b deletion via upregulating fatty acid oxidation (FAO). On a molecular level, Gfi1b epigenetically regulated multiple FAO-related genes. Moreover, we observed that metabolic phenotypes evolved as cells progressed from preleukemia to leukemia, and the correlation between Gfi1b expression level and metabolic phenotype was affected by genetic variations in AML cells. FAO or OXPHOS inhibition significantly impeded leukemia progression of Gfi1b-KO MLL/AF9 cells. Finally, we showed that Gfi1b-deficient AML cells were more sensitive to metformin as well as drugs implicated in OXPHOS and FAO inhibition, opening new potential therapeutic strategies. More... »

PAGES

2196-2207

Journal

TITLE

Leukemia

ISSUE

9

VOLUME

36

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41375-022-01635-9

DOI

http://dx.doi.org/10.1038/s41375-022-01635-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1149326443

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/35804097


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353 Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, 48149, Muenster, Germany
354 rdf:type schema:Organization
355 grid-institutes:grid.461843.c schema:alternateName State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 300052, Tianjin, China
356 schema:name State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 300052, Tianjin, China
357 rdf:type schema:Organization
358 grid-institutes:grid.5718.b schema:alternateName Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
359 schema:name Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
360 Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, 48149, Muenster, Germany
361 rdf:type schema:Organization
362 grid-institutes:grid.5949.1 schema:alternateName Fluorescence Microscopy Facility Muenster (FM)2, Institute of Medical Physics and Biophysics, University of Muenster, 48149, Muenster, Germany
363 Institute of Molecular Tumor Biology, Faculty of Medicine, University of Muenster, 48149, Muenster, Germany
364 Institute of Physiology II, University of Muenster, 48149, Muenster, Germany
365 schema:name Fluorescence Microscopy Facility Muenster (FM)2, Institute of Medical Physics and Biophysics, University of Muenster, 48149, Muenster, Germany
366 Institute of Molecular Tumor Biology, Faculty of Medicine, University of Muenster, 48149, Muenster, Germany
367 Institute of Physiology II, University of Muenster, 48149, Muenster, Germany
368 rdf:type schema:Organization
 




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