Germline Single-Nucleotide Polymorphism <i>GFI1-36N</i> Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia
<b>Background/Objectives</b>: GFI1-36N represents a single-nucleotide polymorphism (SNP) of the zinc finger protein Growth Factor Independence 1 (GFI1), in which the amino acid serine (S) is replaced by asparagine (N). The presence of the <i>GFI1-36N</i> gene variant is assoc...
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2025-01-01
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| author | Jan Vorwerk Longlong Liu Theresa Helene Stadler Daria Frank Helal Mohammed Mohammed Ahmed Pradeep Kumar Patnana Maxim Kebenko Eva Dazert Bertram Opalka Nikolas von Bubnoff Cyrus Khandanpour |
| author_facet | Jan Vorwerk Longlong Liu Theresa Helene Stadler Daria Frank Helal Mohammed Mohammed Ahmed Pradeep Kumar Patnana Maxim Kebenko Eva Dazert Bertram Opalka Nikolas von Bubnoff Cyrus Khandanpour |
| author_sort | Jan Vorwerk |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: GFI1-36N represents a single-nucleotide polymorphism (SNP) of the zinc finger protein Growth Factor Independence 1 (GFI1), in which the amino acid serine (S) is replaced by asparagine (N). The presence of the <i>GFI1-36N</i> gene variant is associated with a reduced DNA repair capacity favoring myeloid leukemogenesis and leads to an inferior prognosis of acute myeloid leukemia (AML) patients. However, the underlying reasons for the reduced DNA repair capacity in <i>GFI1-36N</i> leukemic cells are largely unknown. Since we have demonstrated that GFI1 plays an active role in metabolism, in this study, we investigated whether increased levels of reactive oxygen species (ROS) could contribute to the accumulation of genetic damage in <i>GFI1-36N</i> leukemic cells. <b>Methods</b>: We pursued this question in a murine model of human AML by knocking in human <i>GFI1-36S</i> or <i>GFI1-36N</i> variant constructs into the murine <i>Gfi1</i> gene locus and retrovirally expressing <i>MLL-AF9</i> to induce AML. <b>Results</b>: Following the isolation of leukemic bone marrow cells, we were able to show that the <i>GFI1-36N</i> SNP in our model is associated with enhanced oxidative phosphorylation (OXPHOS), increased ROS levels, and results in elevated γ-H2AX levels as a marker of DNA double-strand breaks (DSBs). The use of free radical scavengers such as N-acetylcysteine (NAC) and α-tocopherol (αT) reduced ROS-induced DNA damage, particularly in <i>GFI1-36N</i> leukemic cells. <b>Conclusions</b>: We demonstrated that the <i>GFI1-36N</i> variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-a9561ac092c7495e8a1ded9b489acaef2025-01-24T13:24:02ZengMDPI AGBiomedicines2227-90592025-01-0113110710.3390/biomedicines13010107Germline Single-Nucleotide Polymorphism <i>GFI1-36N</i> Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid LeukemiaJan Vorwerk0Longlong Liu1Theresa Helene Stadler2Daria Frank3Helal Mohammed Mohammed Ahmed4Pradeep Kumar Patnana5Maxim Kebenko6Eva Dazert7Bertram Opalka8Nikolas von Bubnoff9Cyrus Khandanpour10Department of Hematology and Oncology, University Cancer Center Schleswig-Holstein (UCCSH), University Hospital Schleswig-Holstein, 23562 Lübeck, GermanyDepartment of Hematology, Hemostaseology, Oncology, and Pneumology, West German Cancer Center Essen-Münster (WTZ), University Hospital Münster, 49149 Münster, GermanyDepartment of Hematology and Oncology, University Cancer Center Schleswig-Holstein (UCCSH), University Hospital Schleswig-Holstein, 23562 Lübeck, GermanyDepartment of Hematology, Hemostaseology, Oncology, and Pneumology, West German Cancer Center Essen-Münster (WTZ), University Hospital Münster, 49149 Münster, GermanyDepartment of Hematology and Oncology, University Cancer Center Schleswig-Holstein (UCCSH), University Hospital Schleswig-Holstein, 23562 Lübeck, GermanyDepartment of Hematology and Oncology, University Cancer Center Schleswig-Holstein (UCCSH), University Hospital Schleswig-Holstein, 23562 Lübeck, GermanyDepartment of Hematology and Oncology, University Cancer Center Schleswig-Holstein (UCCSH), University Hospital Schleswig-Holstein, 23562 Lübeck, GermanyDepartment of Hematology and Oncology, University Cancer Center Schleswig-Holstein (UCCSH), University Hospital Schleswig-Holstein, 23562 Lübeck, GermanyDepartment of Hematology and Stem Cell Transplantation, West German Cancer Center Essen-Münster (WTZ), University Hospital Essen, 45147 Essen, GermanyDepartment of Hematology and Oncology, University Cancer Center Schleswig-Holstein (UCCSH), University Hospital Schleswig-Holstein, 23562 Lübeck, GermanyDepartment of Hematology and Oncology, University Cancer Center Schleswig-Holstein (UCCSH), University Hospital Schleswig-Holstein, 23562 Lübeck, Germany<b>Background/Objectives</b>: GFI1-36N represents a single-nucleotide polymorphism (SNP) of the zinc finger protein Growth Factor Independence 1 (GFI1), in which the amino acid serine (S) is replaced by asparagine (N). The presence of the <i>GFI1-36N</i> gene variant is associated with a reduced DNA repair capacity favoring myeloid leukemogenesis and leads to an inferior prognosis of acute myeloid leukemia (AML) patients. However, the underlying reasons for the reduced DNA repair capacity in <i>GFI1-36N</i> leukemic cells are largely unknown. Since we have demonstrated that GFI1 plays an active role in metabolism, in this study, we investigated whether increased levels of reactive oxygen species (ROS) could contribute to the accumulation of genetic damage in <i>GFI1-36N</i> leukemic cells. <b>Methods</b>: We pursued this question in a murine model of human AML by knocking in human <i>GFI1-36S</i> or <i>GFI1-36N</i> variant constructs into the murine <i>Gfi1</i> gene locus and retrovirally expressing <i>MLL-AF9</i> to induce AML. <b>Results</b>: Following the isolation of leukemic bone marrow cells, we were able to show that the <i>GFI1-36N</i> SNP in our model is associated with enhanced oxidative phosphorylation (OXPHOS), increased ROS levels, and results in elevated γ-H2AX levels as a marker of DNA double-strand breaks (DSBs). The use of free radical scavengers such as N-acetylcysteine (NAC) and α-tocopherol (αT) reduced ROS-induced DNA damage, particularly in <i>GFI1-36N</i> leukemic cells. <b>Conclusions</b>: We demonstrated that the <i>GFI1-36N</i> variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage.https://www.mdpi.com/2227-9059/13/1/107acute myeloid leukemiaGFI1single-nucleotide polymorphismmetabolismROS |
| spellingShingle | Jan Vorwerk Longlong Liu Theresa Helene Stadler Daria Frank Helal Mohammed Mohammed Ahmed Pradeep Kumar Patnana Maxim Kebenko Eva Dazert Bertram Opalka Nikolas von Bubnoff Cyrus Khandanpour Germline Single-Nucleotide Polymorphism <i>GFI1-36N</i> Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia Biomedicines acute myeloid leukemia GFI1 single-nucleotide polymorphism metabolism ROS |
| title | Germline Single-Nucleotide Polymorphism <i>GFI1-36N</i> Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia |
| title_full | Germline Single-Nucleotide Polymorphism <i>GFI1-36N</i> Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia |
| title_fullStr | Germline Single-Nucleotide Polymorphism <i>GFI1-36N</i> Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia |
| title_full_unstemmed | Germline Single-Nucleotide Polymorphism <i>GFI1-36N</i> Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia |
| title_short | Germline Single-Nucleotide Polymorphism <i>GFI1-36N</i> Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia |
| title_sort | germline single nucleotide polymorphism i gfi1 36n i causes alterations in mitochondrial metabolism and leads to increased ros mediated dna damage in a murine model of human acute myeloid leukemia |
| topic | acute myeloid leukemia GFI1 single-nucleotide polymorphism metabolism ROS |
| url | https://www.mdpi.com/2227-9059/13/1/107 |
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