Systemic mastocytosis is a hematopoietic neoplasm driven by oncogenic activation of the KIT tyrosine kinase, characterized by the excessive accumulation of abnormal mast cells in various organs and, most notably, the bone marrow. Its clinical spectrum is broad, ranging from indolent forms, in which life expectancy remains normal and symptoms arise primarily from the release of mast cell mediators, to advanced forms with a poor prognosis, marked by tissue infiltration and organ failure. The KIT D816V mutation is a major cause of the disease, but its presence across most clinical forms argues against a decisive role in progression. While secondary genetic, epigenetic, and microenvironmental alterations have been proposed, the metabolic underpinnings of aggressiveness had remained largely unknown, hampering the identification of actionable dependencies when KIT-targeted therapies fail.
By analyzing the plasma metabolomic profile of patients, the authors show that it can distinguish indolent from advanced forms. Among the metabolites examined, N-acetyl-D-glucosamine (GlcNAc) emerges as the most predictive of severity. Elevated plasma GlcNAc levels in patients with advanced forms are accompanied by activation of the GlcNAc-fueled hexosamine biosynthesis pathway in bone marrow aspirates and purified bone marrow mast cells. Functionally, GlcNAc stimulates the proliferation of human neoplastic mast cells and precipitates health deterioration in a humanized mouse model of the disease. In the presence of GlcNAc, immunoglobulin E–stimulated mast cells release greater amounts of pro-inflammatory cytokines and trigger a stronger acute response in a mouse model of passive cutaneous anaphylaxis.
Mechanistically, elevated GlcNAc increases the transcriptional accessibility of chromatin regions containing genes encoding mediators of receptor tyrosine kinase cascades and inflammatory responses, among which the MAPK pathway is the most represented. The authors thereby establish a link between purine and pyrimidine metabolism and RTK signaling. They further discuss the likely exogenous origin of GlcNAc, in particular the microbiota—GlcNAc being a constituent of bacterial peptidoglycan—whose release would be promoted by the intestinal hyperpermeability associated with mast cell mediators, fueling a vicious cycle of inflammation. The possibility of a TET2 loss of function through aberrant O-GlcNAcylation is also raised as a hypothesis to be explored.
This work identifies GlcNAc as an oncometabolite promoting the aggressiveness of systemic mastocytosis and underscores the potential therapeutic value of targeting metabolic pathways to modulate mast cell effector functions in mast cell–associated diseases.