Epigenetic changes can contribute to development of acute myeloid leukemia (AML), a malignant disease of the bone marrow. A single-nucleotide polymorphism of transcription factor growth factor independence 1 (GFI1) generates a protein with an asparagine at position 36 (GFI136N) instead of a serine at position 36 (GFI136S), which is associated with de novo AML in humans. However, how GFI136N predisposes to AML is poorly understood. To explore the mechanism, we used knock-in mouse strains expressing GFI136N or GFI136S. Presence of GFI136N shortened the latency and increased the incidence of AML in different murine models of myelodysplastic syndrome/AML. On a molecular level, GFI136N induced genomewide epigenetic changes, leading to expression of AML-associated genes. On a therapeutic level, use of histone acetyltransferase inhibitors specifically impeded growth of GFI136N-expressing human and murine AML cells in vitro and in vivo. These results establish, as a proof of principle, how epigenetic changes in GFI136N-induced AML can be targeted.
Botezatu, L., Michel, L. C., Helness, A., Vadnais, C., Makishima, H., Hönes, J. M., … Khandanpour, C. (2016). Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML. Experimental Hematology, 44(8), 713-726.e14. https://doi.org/10.1016/j.exphem.2016.05.004