Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition.

Autor:	Vorwerk J; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany., Sun K; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany., Frank D; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany., Neumann F; Fluorescence Microscopy Facility Münster, Institute of Medical Physics and Biophysics, University of Münster, Münster, Germany.; Evorion Biotechnologies GmbH, Münster, Germany., Hüve J; Fluorescence Microscopy Facility Münster, Institute of Medical Physics and Biophysics, University of Münster, Münster, Germany., Budde PM; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany., Liu L; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany., Xie X; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany., Patnana PK; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany., Ahmed HMM; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany., Opalka B; Department of Hematology and Stem Cell Transplantation, West German Cancer Center (WTZ), University Hospital Essen, Essen, Germany., Lenz G; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany., Jayavelu AK; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Munich, Germany.; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, Heidelberg, Germany.; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Clinical Cooperation Unit Pediatric Leukemia, German Cancer Research Center (DKFZ), Heidelberg, Germany., Khandanpour C; Department of Medicine A, Hematology, Hemostaseology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany.; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Aug 08; Vol. 12, pp. 903691. Date of Electronic Publication: 2022 Aug 08 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.903691
Abstrakt:	The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1 , GFI1-36N , has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro . As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib. Competing Interests: FN was employed by evorion biotechnologies GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Vorwerk, Sun, Frank, Neumann, Hüve, Budde, Liu, Xie, Patnana, Ahmed, Opalka, Lenz, Jayavelu and Khandanpour.)
Databáze:	MEDLINE
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