Vitamin C induced epigenomic remodelling in IDH1 mutant acute myeloid leukemia

The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating TET2 mutations and neomorphic IDH mutations are recurrent and mutually exclusive in acute myeloid leukemia genomes. Ascorbic Acid (vitamin C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus we sought to explore its effect in a leukemic model expressing IDH1R132H. Vitamin C treatment induced a reduction in cell proliferation and an increase in the expression of genes involved in leukocyte differentiation in IDH1R132H expressing cells. Genome-wide assessment of 5mC and 5hmC revealed a set of vitamin C induced differentially methylated regions (DMRs), many of which displayed demethylation at myeloid enhancers and regions containing binding elements for the hematopoietic transcription factors RUNX1 and PU.1. We observed a significant loss of PU.1 DNA binding and an increase of RUNX1 binding that was accompanied by demethylation at RUNX1 binding sites within enhancers. Genome-wide profiling of histone modifications revealed a negative correlation between H3K4 methylation and DNA methylation at vitamin C induced DMRs. In addition, vitamin C induced an increase in H3K27ac flanking sites bound by RUNX1. Taken together our results suggest that vitamin C is able to stimulate epigenetic remodelling of transcription factor binding sites and regulatory elements to drive differentiation in a leukemic model.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat