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GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia
GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia
- Source :
- Leukemia; September 2022, Vol. 36 Issue: 9 p2196-2207, 12p
- Publication Year :
- 2022
-
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 Gfi1bdeletion. Here we explored the role of Gfi1b in metabolism reprogramming during hematopoiesis and leukemogenesis. We demonstrated that Gfi1bdeletion remarkably activated mitochondrial respiration and altered energy metabolism dependence toward oxidative phosphorylation (OXPHOS). Mitochondrial substrate dependency was shifted from glucose to fatty acids upon Gfi1bdeletion 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/AF9cells. 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.
Details
- Language :
- English
- ISSN :
- 08876924 and 14765551
- Volume :
- 36
- Issue :
- 9
- Database :
- Supplemental Index
- Journal :
- Leukemia
- Publication Type :
- Periodical
- Accession number :
- ejs60348271
- Full Text :
- https://doi.org/10.1038/s41375-022-01635-9