Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML

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 (GFI1 36N ) instead of a serine at position 36 (GFI1 36S ), which is associated with de novo AML in humans. However, how GFI1 36N predisposes to AML is poorly understood. To explore the mechanism, we used knock-in mouse strains expressing GFI1 36N or GFI1 36S . Presence of GFI1 36N shortened the latency and increased the incidence of AML in different murine models of myelodysplastic syndrome/AML. On a molecular level, GFI1 36N induced genomewide epigenetic changes, leading to expression of AML-associated genes. On a therapeutic level, use of histone acetyltransferase inhibitors specifically impeded growth of GFI1 36N -expressing human and murine AML cells in vitro and in vivo. These results establish, as a proof of principle, how epigenetic changes in GFI1 36N -induced AML can be targeted.