Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia

Abstract

The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating ten-eleven translocation 2 (TET2) mutations and neomorphic isocitrate dehydrogenase (IDH) mutations are recurrent and mutually exclusive in acute myeloid leukaemia 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 leukaemic model expressing IDH1R132H. Vitamin C treatment induced an IDH1R132H-dependent reduction in cell proliferation and an increase in expression of genes involved in leukocyte differentiation. Vitamin C induced differentially methylated regions that displayed a significant overlap with enhancers implicated in myeloid differentiation and were enriched in sequence elements for the haematopoietic transcription factors CEBPβ, HIF1α, RUNX1 and PU.1. Chromatin immunoprecipitation sequencing of PU.1 and RUNX1 revealed a significant loss of PU.1 and increase of RUNX1-bound DNA elements accompanied by their demethylation following vitamin C treatment. In addition, vitamin C induced an increase in H3K27ac flanking sites bound by RUNX1. On the basis of these data we propose a model of vitamin C-induced epigenetic remodelling of transcription factor-binding sites driving differentiation in a leukaemic model.

Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

“…In some cases, there have been no benefits. However, new knowledge regarding the pharmacokinetic properties of Vit-C, and recent preclinical studies, have revived interest in the utilization of high-dose Vit-C for cancer treatment [132][133][134][135][136][137][138][139][140][141][142][143][144][145]. Similar is the case of using IV Vit-C as antiviral, especially for the recent Covid19 [146][147][148][149][150].…”

Drug persistence – From antibiotics to cancer therapies

“…These findings are particularly intriguing given that epigenetic and metabolic changes seem to be closely linked in many cancers. A prime example are mutations in metabolic enzymes, such as isocitrate dehydrogenase 1 and 2, which can modulate the epigenetic state of cells through the accumulation of ‘oncometabolites’ such as 2-hydroxyglutarate, and thereby influence cancer progression and drug survival [48,49]. The involvement of EMT and chromatin remodeling suggests the requirement for a distinct regulatory program to ensure the formation and/or maintenance of a persister state, analogous to the aforementioned stringent response dependent regulation in bacterial persisters.…”

Reduced plasma ascorbic acid levels in recipients of myeloablative conditioning and hematopoietic cell transplantation

“…A critically important recent discovery is that AA controls leukemic cell proliferation and differentiation, particularly in TET2 and IDH1 mutated AML. This effect is mediated through epigenetic control of transcription factor binding sites in leukemia . These results suggest that post‐transplant AA repletion may augment immune reconstitution and contribute to the control of hematological malignancies.…”