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.
| Original language | English |
|---|---|
| Journal | Leukemia |
| Volume | 36 |
| Issue number | 9 |
| Pages (from-to) | 2196-2207 |
| Number of pages | 12 |
| ISSN | 0887-6924 |
| DOIs | |
| Publication status | Published - 09.2022 |
Funding
The authors thank the animal facility of University Hospital Muenster. We also thank Dagmar Clemens and Hannelore Leuschke from University Hospital Muenster for their technical assistance, Prof. Stephan Hailfinger for editing the manuscript, Di Liu from Hannover Medical School for providing the schematic draft of mouse, and Wolfgang A. Linke (Institute of physiology II, University of Muenster) for TEM support. The work was supported by the Deutsche Krebshilfe (70112392), and partially by the Jose Carreras Leukämie Stiftung (DJCLS 17R/2018), Deutsche Forschungsgemeinschaft (KH331/2–3), and the intramural funding of the faculty of Medicine at University Hospital of Muenster (Kha2/002/20). Figures , , , , and and Supplementary Figs. and were created with BioRender.com. The authors thank the animal facility of University Hospital Muenster. We also thank Dagmar Clemens and Hannelore Leuschke from University Hospital Muenster for their technical assistance, Prof. Stephan Hailfinger for editing the manuscript, Di Liu from Hannover Medical School for providing the schematic draft of mouse, and Wolfgang A. Linke (Institute of physiology II, University of Muenster) for TEM support. The work was supported by the Deutsche Krebshilfe (70112392), and partially by the Jose Carreras Leukämie Stiftung (DJCLS 17R/2018), Deutsche Forschungsgemeinschaft (KH331/2–3), and the intramural funding of the faculty of Medicine at University Hospital of Muenster (Kha2/002/20). Figures 1a , 4a , 4e , 5a , and 7d and Supplementary Figs. S8a and S12 were created with BioRender.com.
Research Areas and Centers
- Research Area: Luebeck Integrated Oncology Network (LION)
- Centers: University Cancer Center Schleswig-Holstein (UCCSH)
DFG Research Classification Scheme
- 2.22-14 Hematology, Oncology
