Conclusions
We demonstrated that the GFI1-36N variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage.
Methods
We pursued this question in a murine model of human AML by knocking in human GFI1-36S or GFI1-36N variant constructs into the murine Gfi1 gene locus and retrovirally expressing MLL-AF9 to induce AML.
Results
Following the isolation of leukemic bone marrow cells, we were able to show that the GFI1-36N 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 GFI1-36N leukemic cells. Conclusions: We demonstrated that the GFI1-36N variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage.