Germline Single-Nucleotide Polymorphism Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia

Overview

Journal Biomedicines

Date 2025 Jan 25

PMID 39857691

Authors

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

Affiliations

Soon will be listed here.

Abstract

: 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 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 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 leukemic cells. : We pursued this question in a murine model of human AML by knocking in human or variant constructs into the murine gene locus and retrovirally expressing to induce AML. : Following the isolation of leukemic bone marrow cells, we were able to show that the 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 leukemic cells. : We demonstrated that the variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage.

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