Ascorbate Inhibits Proliferation and Promotes Myeloid Differentiation in TP53-Mutant Leukemia

Abstract

Loss-of-function mutations in the DNA demethylase TET2 are associated with the dysregulation of hematopoietic stem cell differentiation and arise in approximately 10% of de novo acute myeloid leukemia (AML). TET2 mutations coexist with other mutations in AML, including TP53 mutations, which can indicate a particularly poor prognosis. Ascorbate can function as an epigenetic therapeutic in pathological contexts involving heterozygous TET2 mutations by restoring TET2 activity. How this response is affected when myeloid leukemia cells harbor mutations in both TET2 and TP53 is unknown. Therefore, we examined the effects of ascorbate on the SKM-1 AML cell line that has mutated TET2 and TP53. Sustained treatment with ascorbate inhibited proliferation and promoted the differentiation of these cells. Furthermore, ascorbate treatment significantly increased 5-hydroxymethylcytosine, suggesting increased TET activity as the likely mechanism. We also investigated whether ascorbate affected the cytotoxicity of Prima-1Met, a drug that reactivates some p53 mutants and is currently in clinical trials for AML. We found that the addition of ascorbate had a minimal effect on Prima-1Met–induced cytotoxicity, with small increases or decreases in cytotoxicity being observed depending on the timing of treatment. Collectively, these data suggest that ascorbate could exert a beneficial anti-proliferative effect on AML cells harboring both TET2 and TP53 mutations whilst not interfering with targeted cytotoxic therapies such as Prima-1Met.

The Epigenetic Role of Vitamin C in Neurodevelopment

“…Increased activity in vitro [101,112], in cell culture [101,102,114,117,120], in mice [121,122], and in a clinical setting [123] Regulation of haematopoiesis, mutations are a driver of leukaemia and other haematopoietic pathologies [95,121,[124][125][126].…”

“…The relationship between vitamin C and TET activity has recently attracted attention in the context of leukaemia research, where vitamin C supplementation is being investigated as a form of epigenetic therapy to enhance TET2 activity in models of leukaemia characterised by decreased TET2 activity [95,121,122,124]. However, despite extensive research, the exact role of vitamin C in the TET catalytic cycle is unknown.…”

Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products

“…Regarding RCT trial, normalization of plasma vitamin C by oral supplementation leads to an increase in the 5hmC/5mC ratio compared to placebo-treated patients [ 114 ]. Vitamin C expressed anti-proliferative effects for AML cells with both TET2 and TP53 mutations [ 115 ]. However, currently, large scale clinical trial data are required to establish the clinical anti-proliferative effect of vitamin C in AML patients.…”

Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment

“…Clonal heterogeneity and metabolic heterogeneity are, in general, associated with the failure of anti-cancer drugs, including metabolic inhibitors [14][15][16]. However, the metabolic reprogramming occurring in AML hematopoietic stem cells depends on their genetic characteristics, and thus represents a promising target for treatment [17][18][19][20][21]. In this study, we compared the metabolic pathways underlying the different stages of differentiation of normal myeloid progenitors/precursors with that of primary blasts from six AML patients and of five AML cell lines featuring different genetic mutations commonly associated with AMLs, and diverse metabolic phenotypes.…”

“…Hexokinase 1 and 2 (HK1/HK2) are also associated with the mitochondrial membrane permeability transition pore (PTP) and prevents apoptosis, thus controlling reactive oxygen species (ROS) formation [29]. Recent studies reported the capacity of ascorbate to target leukemia-initiating cells [20,21].…”