GlcNAc is a mast-cell chromatin-remodeling oncometabolite that promotes systemic mastocytosis aggressiveness.

Systemic mastocytosis (SM) is a KIT-driven hematopoietic neoplasm characterized by the excessive accumulation of neoplastic mast cells (MCs) in various organs and, mainly, the bone marrow (BM). Multiple genetic and epigenetic mechanisms contribute to the onset and severity of SM. However, little is known to date about the metabolic underpinnings underlying SM aggressiveness, which has thus far impeded the development of strategies to leverage metabolic dependencies when existing KIT-targeted treatments fail. Here, we show that plasma metabolomic profiles were able to discriminate indolent from advanced forms of the disease. We identified N-acetyl-d-glucosamine (GlcNAc) as the most predictive metabolite of SM severity. High plasma levels of GlcNAc in patients with advanced SM correlated with the activation of the GlcNAc-fed hexosamine biosynthesis pathway in patients BM aspirates and purified BM MCs. At the functional level, GlcNAc enhanced human neoplastic MCs proliferation and promoted rapid health deterioration in a humanized mouse model of SM. In addition, in the presence of GlcNAc, immunoglobulin E-stimulated MCs triggered enhanced release of proinflammatory cytokines and a stronger acute response in a mouse model of passive cutaneous anaphylaxis. Mechanistically, elevated GlcNAc levels promoted the transcriptional accessibility of chromatin regions that contain genes encoding mediators of receptor tyrosine kinases cascades and inflammatory responses, thus leading to a more aggressive phenotype. Therefore, GlcNAc is an oncometabolite driver of SM aggressiveness. This study suggests the therapeutic potential for targeting metabolic pathways in MC-related diseases to manipulate MCs effector functions.

Evaluation of vitamin D bioaccessibility and mineral solubility from test meals containing meat and/or cereals and/or pulses using in vitro digestion.

In this study, we evaluated vitamin D and mineral (iron, zinc, magnesium) transfer to the bolus aqueous phase during the digestion of meals with/without pulses. We performed in vitro digestions using test meals made either of i) beef and/or semolina and/or chickpeas, or of ii) potatoes supplemented or not with fibers, phytates, tannins and saponins. Chickpea presence led to a decrease in vitamin D bioaccessibility (-56%, p ≤ 0.05) and mineral solubility (-28% for iron, p ≤ 0.05) compared with meals with beef and/or semolina only. This effect was largely compensated for vitamin D by the fact that this vitamin was more stable during digestion of meals based on plant foods only than of meals with beef. Tannins were the most deleterious compounds for iron solubility, while phytates and tannins decreased vitamin D bioaccessibility. Agronomical or technical solutions to selectively decrease the amount in pulses of compounds that affect micronutrient bioavailability should be further explored.