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

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.

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

“… 2,4 Subsequently, metabolic alterations were measured in GFI1 ‐KI and ‐KD mice‐derived lin‐ cells. The influence of the GFI1 expression on oxidative phosphorylation (OXPHOS) was analysed using seahorse mitostress and glycostress assays (oxygen consumption rate (OCR) and extracellular acidification rate (ECAR)) as previously described 7 …”

“…Fatty acid oxidation (FAO), glucose and glutamine metabolism pathways contribute to OXPHOS. We therefore used inhibitors; etomoxir, UK5099 and BPTES to target these pathways, respectively, as previously described 7,10–12 . The response rate was measured as the rate of OCR reduction upon inhibitor treatment (Figure 1E,F).…”

“…We have also recently shown that the loss of GFI1b, a closely related protein of GFI1, promotes OXPHOS through enhanced FAO. 7 The expression of GFI1 and GFI1b is lineage and celldependent. 51,52 GFI1b is predominantly expressed in HSCs and megakaryocyte-erythrocyte progenitor cells, whereas GFI1 is highly expressed in the cells of the myeloid lineage.…”

Enhanced MCM5 Level Predicts Bad Prognosis in Acute Myeloid Leukemia

“…AML is listed among the most common hematologic malignancies [29,30]. Despite progress in the treatment of AML, it remains difficult to treat and cure, and the 5-year overall survival rate, especially in sufferers which age is over 60 years, is still very low [31][32][33]. The pathogenesis, diagnosis and treatment of AML are hot topics in current research.…”

LSD1 inhibition modulates transcription factor networks in myeloid malignancies

“…Gfi1b deletion significantly activated OxPhos and altered the energy metabolism of cells to rely more on oxidative phosphorylation, causing cells to shift their dependency on glucose for energy to using fatty acids through the upregulation of FAO. The progression from preleukemia to leukemia was accompanied by changes in the metabolic phenotype and interestingly, genetic variations in AML cells were found to have a great influence on the correlation between Gfi1b expression and the metabolic phenotype (50). This suggests that the role of Gfi1b in regulating energy metabolism in hematopoietic and leukemic cells may be dynamic and may vary depending on the specific stage of disease progression and the genetic characteristics of the AML.…”