Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate ...and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.
Abstract
TET2 loss-of-function mutations induce a pre-malignant state known as clonal hematopoiesis of indeterminate potential (CHIP). CHIP occurs in approximately 10% of people over 65 years of age ...and confers a 10-fold greater risk of developing hematological malignancy. Several environmental factors, including radiation, sleep deprivation, atherosclerosis, and diet, have been associated with the expansion of pre-malignant clones in CHIP patients. Tet2-deficiency in mice has also been shown to trigger a pro-inflammatory state with increased intestinal permeability and accelerated myeloid expansion. Gut microbes exert an influence on host disease progression through the synthesis of many compounds including short-chain fatty acids (SCFAs), which promote gut barrier integrity. Dietary levels of one-carbon metabolites and cofactors, including methionine and folate, have been found to alter gut microbial composition in disease-free adults and influence SCFA production in the gut in murine models. Given the connection between diet, SCFAs and gut permeability, we sought to determine the impact of dietary one-carbon metabolites on gut microbial composition and function in a murine model of pre-malignant hematopoiesis. We performed competitive bone marrow transplantation assays in mice fed diets with altered one-carbon metabolite supplementation, such as high and low folate or methionine. We found that differential supplementation with these one-carbon metabolites did not influence the competitiveness of Tet2-deficient hematopoietic cells, however, increased dietary methionine promoted a myeloid lineage differentiation bias and an elevation in circulating pro-inflammatory cytokines. After 8 months of dietary treatment, fecal samples were collected, and shotgun sequencing was performed to examine the role of one-carbon metabolite levels on gut microbial diversity. Alterations in dietary methionine and folate caused significant changes to gut microbial composition in Tet2-deficient mice. High folate or methionine supplementation led to a decrease in the ratio of Firmicutes to Bacteroidetes and high folate supplementation was also associated with decreased alpha diversity and a decrease in SCFA-producing bacteria in the gut. These studies highlight the potential influence of dietary one-carbon metabolites on the microbiome and inflammatory microenvironment of pre-malignant hematopoiesis.
Citation Format: Peter Lyon, Praveen Singh, Byron Fang, Victoria Strippoli, Sabita Roy, Luisa Cimmino. The influence of dietary one-carbon metabolites on gut dysbiosis during pre-malignant hematopoiesis abstract. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A44.
TET2 haploinsufficiency is a driving event in myeloid cancers and associated with a worse prognosis in patients with AML. Enhancing residual TET2 activity using vitamin C increases oxidized ...5-methylcytosine (oxi-mC) formation and promotes active DNA demethylation via base-excision repair (BER) that slows leukemia progression. We utilized genetic and compound library screening approaches to identify rational combination treatment strategies to improve the use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of multiple FDA approved drugs, vitamin C treatment with poly-ADP-ribose polymerase inhibitors (PARPi) elicited a strong synergistic effect at blocking AML self-renewal in murine and human models. AML cells treated with a combination of vitamin C and PARPi in vitro led to reduced replating capacity in colony-forming assays, reduced viability in liquid culture, and increased survival upon treatment in vivo. These phenotypes were associated with increased p21 expression, cell-cycle stalling in S-phase and differentiation of AML cells toward a more mature myeloid phenotype. Furthermore, we show that vitamin C-mediated TET activation combined with PARPi causes an enrichment of chromatin-bound PARP1 protein specifically at 5-formylcytosine (5fC) oxi-mCs, and an enrichment for yH2AX at these sites in addition to its accumulation during mid-S phase. This work provides the first proof of PARP1 as a direct reader of 5fC, and enrichment of 5fC at sites marked by yH2AX. The generation of BER-inducing oxi-mCs imparts a novel therapeutic potential of PARPi, which are currently in clinical trial to determine their therapeutic efficacy for AML. Given the majority of AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant to improve treatment outcome.
ABSTRACT
Aim: We evaluated the association between fluid and nutrient intake and chronic kidney disease (CKD).
Methods: Two cross‐sectional population‐based studies. Validated nutrition food ...frequency questionnaires (FFQ) administered to people >50 years, identified in a door‐to‐door census of a well‐defined suburban area. Based upon nutrition tables we calculated intakes of over 40 nutrients (factors) and total daily energy intake. Primary outcome was CKD. Fluid (total content of fluid and drinks assessed in the FFQ) and nutrient intake was stratified in quintiles and association with CKD analysed by logistic regression, expressed as unadjusted and adjusted odds ratios, with testing for linear trend.
Results: The proportion of participants who completed the FFQ and had glomerular filtration rate (GFR) measures was 2744/3654 (75.0%) for the first and 2476/3508 (70.6%) for the second survey. CKD was present in 12.4–23.5% men and 14.9–28.7% women (mean ages 66.4–65.4 years), respectively. Participants who had the highest quintile of fluid intake (3.2 L/day) had a significantly lower risk of CKD (odds ratio 0.5, 95%CI 0.32 to 0.77, P for trend = 0.003). These findings were consistent across both study periods, both equations to calculate GFR and both GFR thresholds.
Conclusion: Higher intakes of fluid appear to protect against CKD. CKD may be preventable at a population level with low‐cost increased fluid intake.
It is unclear whether increasing fluid intake will slow the progression of chronic kidney disease. In this issue, Strippoli and co‐workers examine this important question using the Blue Mountains observational cohort consisting of more than 2500 patients in Western Sydney. The results show that subjects who drank more than 3.2 L per day had a lower risk of chronic kidney disease (OR 0.5, 95%CI 0.32–0.77).
Maritime trade is the backbone of the world’s economy. Around ninety percent of all goods are transported by ship, and since World War II shipbuilding has undergone major changes in response to new ...commercial pressures and opportunities. Early British dominance, for example, was later undermined by competition from the Japanese, who have since been overtaken by South Korea and, most recently, China. The case studies in this volume trace these and other important developments in the shipbuilding and ship repair industries, as well as workers’ responses to these historic transformations.
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