Abstract
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.
| Original language | English |
|---|---|
| Journal | British Journal of Haematology |
| Volume | 202 |
| Issue number | 5 |
| Pages (from-to) | 1033-1048 |
| Number of pages | 16 |
| ISSN | 0007-1048 |
| DOIs | |
| Publication status | Published - 09.2023 |
Funding
HCR received consulting and lecture fees from Abbvie, AstraZeneca, Vertex and Merck. HCR received research funding from Gilead Pharmaceuticals. H.C.R. is a cofounder of CDL Therapeutics GmbH. The remaining authors declare no competing financial interest. The authors thank the Core Facility Genomics of the University of Muenster for RNA sequencing. We also thank Klaus Lennartz, Thorsten König and Annegret Rosemann for providing support with FACS cell sorting. The authors also thank Renata Köster, Dagmar Clemens and Hannelore Leuschke for their continuous technical support in the lab. We thank Prof. Dr. Med. Georg Lenz, University Hospital Münster, for providing the modified cell line THP-1 and the plasmid pRSMX-PG and Prof. Dr. Frank Rosenbauer, Institute of Molecular Tumour Biology, Münster, for providing the FACS facility and ATACseq analysis. We also thank Prof. Dr. med. Helmut Hanenberg for providing the plasmids pCD/NL-BH, pcoPE and pCL6-IRES-EGwo backbone for lentiviral-based overexpression of GFI1 in leukaemic cell lines. The graphical abstract was ‘Created with BioRender.com’. JTS is grateful for support by the German Cancer Consortium (DKTK), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; #405344257/SI 1549/3-2 and SI1549/4-1) and Wilhelm-Sander Stiftung (grant number: 2019.008.1; to J.T.S. and M. T.-A.). Open Access funding enabled and organized by Projekt DEAL. The work was supported by the Jose Carreras Leukämie Foundation (DJCLS 17R/2018), partially by the Deutsche Krebshilfe (70112392), Deutsche Forschungsgemeinschaft (KH331/2–3) and the intramural funding of the faculty of Medicine at University Hospital of Muenster (Kha2/002/20). JTS is grateful for support by the German Cancer Consortium (DKTK), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; #405344257/SI 1549/3–2 and SI1549/4–1) and Wilhelm‐Sander Stiftung (grant number: 2019.008.1; to J.T.S. and M. T.‐A.).
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
