Fig. 1

Study of vitamin C supplementation in individuals with germline TET2 mutations. A Pedigree (details modified for confidentiality) showing TET2 c.4500delA mutation statuses (+ / + control, +/− mutation carrier) and the individuals previously treated for nodular lymphocyte-predominant Hodgkin lymphoma (filled symbols). Males (square); females (circle). The individuals sampled for this study are marked with a 'Ly' patient ID. B A schematic drawing showing the study plan and information on the study individuals. C Regulation of DNA methylation. Cytosine (C) is methylated by DNA methyltransferases (DNMTs) into 5-methylcytosine (5-mC). Demethylation can occur passively (dashed lines) during cell division or actively via oxidation by the ten–eleven translocation (TET) enzymes, including TET2, resulting in generation of 5-hydroxymethylcytosine (5-hmC) and its further oxidation products 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). TETs are dependent on the availability of cofactors α-ketoglutarate (α-KG) and Fe²⁺. Ascorbic acid (vitamin C) enhances TET activity, likely by maintaining the redox state of Fe²⁺, resulting in increased production of all 5-mC oxidation products [5,6,7, 10]. Only 5-fC and 5-caC can be actively converted to unmethylated C via excision by thymine DNA glycosylase (TDG). The resulting abasic site is repaired into C via the base excision repair (BER) pathway