Abstract
Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)–directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.
| Originalsprache | Englisch |
|---|---|
| Zeitschrift | Blood |
| Jahrgang | 142 |
| Ausgabenummer | 25 |
| Seiten (von - bis) | 2175-2191 |
| Seitenumfang | 17 |
| ISSN | 0006-4971 |
| DOIs | |
| Publikationsstatus | Veröffentlicht - 21.12.2023 |
Fördermittel
The authors thank the Core Facility Genomics of the University Muenster and Genomics and Transcriptomics Facility for RNA sequencing. Furthermore, the authors also thank the Imaging Center Essen and the Fluorescence Microscopy Facility Münster for guidance and providing the microscopes. The authors also thank Maria Eynck, Renata Köster, Dagmar Clemens, Hannelore Leuschke, and Claudia Dill for their technical assistance, and Klaus Lennartz and Thorsten König for their assistance with cell sorting. The authors thank the members of Proteomics and Signal Transduction Department at the Max Planck Institute for Biochemistry, particularly Igor Paron for his technical support. H.B. and A.K. acknowledge computational support from the OMICS compute cluster at the University of Lübeck. 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). This study was supported by AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ, who are codeveloping olaparib. J. Vorwerk was supported by the Jürgen Manchot Foundation and the Medizinerkolleg Münster. A.K.J. and M.M. were supported by the Max Planck Society for the Advancement of Science and by the German Research Foundation (Gottfried Wilhelm Leibniz Prize). A.K.J. is supported by DFG Emmy Noether grant (JA3274/1-1). H.B. was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy EXC 22167-390884018, partially funded by the Bundesministerium für Bildung und Forschung grant 01ZZ1804B (DIFUTURE) (A.M.N.B.). Contribution: D.F. J. Vorwerk, L.M. L.M.G. N.J. Y.A.-M. P.K.P. H.M.M.A. L.L. X.X. K.S. L.M.G. E.W. J.T. F.S. L.R. and A.K.J. performed experimental research; D.F. F.C.C. H.A. M.G. M.S. and D.K. genotyped human patient samples; D.F. J. Vorwerk, J.H. and F.N. took the fluorescence images; D.F. J.M.F. A.K. H.M. S.H. L.W. V.C. E.W. S.K.M. J.W.T. A.K.J. T.L. and C.K. performed data analysis, presentation, and interpretation; A.F. performed data analysis and edited the manuscript; C.R. provided samples, performed data analysis, and edited the manuscript; N.v.B. and G.L. provided funding and samples, analysed data, and edited the manuscript; A.M.N.B. R.A. and T.H. performed bioinformatics analyses; H.B. G.H. M.D. M.K. and J. Varghese supervised and supported bioinformatics analyses; R.R. provided essential mouse strains and performed the analysis of the mouse model; J.T. performed the immunostaining, the measurements and the evaluation of the O6MeG assays; A.K.J. L.M. M.K. T.H. and J.M.F. performed mass spectrometry experiments, data analysis, and bioinformatics; A.K.J. and M.M. provided support and supervised the mass spectrometry experiments; V.C. and T.M. analyzed GFI1-binding sites in hematopoietic precursor cells; M.H. F.T. G.G. D.S. J.T. F.S. W.E.B. J.K. F.R. A.K. M.D. U.D. M.M. A.K.J. M.H. J. Vorwerk, H.C.R. and C.K. provided essential data or samples or research support; D.F. A.K.J. and C.K. designed the study and wrote the manuscript; S.C.N. B.O. and T.M. critically revised the article; and all authors read, provided critical comments, and approved the manuscript. The authors thank the Core Facility Genomics of the University Muenster and Genomics and Transcriptomics Facility for RNA sequencing. Furthermore, the authors also thank the Imaging Center Essen and the Fluorescence Microscopy Facility Münster for guidance and providing the microscopes. The authors also thank Maria Eynck, Renata Köster, Dagmar Clemens, Hannelore Leuschke, and Claudia Dill for their technical assistance, and Klaus Lennartz and Thorsten König for their assistance with cell sorting. The authors thank the members of Proteomics and Signal Transduction Department at the Max Planck Institute for Biochemistry, particularly, Igor Paron for his technical support. H.B. and A.K. acknowledge computational support from the OMICS compute cluster at the University of Lübeck. 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 ). This study was supported by AstraZeneca and Merck Sharp & Dohme Corp , a subsidiary of Merck & Co Inc, Kenilworth, NJ, who are codeveloping olaparib. J. Vorwerk was supported by the Jürgen Manchot Foundation and the Medizinerkolleg Münster . A.K.J. and M.M. were supported by the Max Planck Society for the Advancement of Science and by the German Research Foundation (Gottfried Wilhelm Leibniz Prize). A.K.J. is supported by DFG Emmy Noether grant ( JA3274/1-1 ). H.B. was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy EXC 22167-390884018 , partially funded by the Bundesministerium für Bildung und Forschung grant 01ZZ1804B (DIFUTURE) (A.M.N.B.).
| Träger | Trägernummer |
|---|---|
| AstraZeneca | |
| Merck Sharp and Dohme United Kingdom | |
| Jürgen Manchot Stiftung | |
| Deutsche Forschungsgemeinschaft (DFG) | JA3274/1-1, KH331/2-3, Kha2/002/20, EXC 22167-390884018 |
| Bundesministerium für Bildung und Forschung | 01ZZ1804B |
| Max-Planck-Gesellschaft | |
| José Carreras Leukämie-Stiftung | 17R/2018 |
| Deutsche Krebshilfe | 70112392 |
| Max-Planck-Institut für Biogeochemie |
Strategische Forschungsbereiche und Zentren
- Profilbereich: Lübeck Integrated Oncology Network (LION)
- Zentren: Universitäres Cancer Center Schleswig-Holstein (UCCSH)
DFG-Fachsystematik
- 2.22-14 Hämatologie, Onkologie
UN SDGs
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