TNF alpha promotes clonal dominance of KIT D816V+ cells in mastocytosis: role of survivin and impact on prognosis.

Systemic mastocytosis (SM) is defined by expansion and accumulation of neoplastic mast cells (MC) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor independent KIT activation and accumulation of MC. Tumor necrosis factor-alpha (TNF) is a pro-apoptotic and inflammatory cytokine that has been implicated in clonal selection of neoplastic cells. We found that KIT D816V increases expression and secretion of TNF. TNF expression in neoplastic MC is reduced by KIT-targeting drugs. Similarly, knockdown of KIT or targeting the downstream signaling cascade of MAPK and NF-κB signaling reduced TNF expression levels. TNF reduces colony formation of human BM cells while KIT D816V+ cells are less susceptible to the cytokine potentially contributing to clonal selection. In line, knockout of TNF in neoplastic MC prolonged survival and reduced myelosuppression in a murine xenotransplantation model. Mechanistic studies revealed that the relative resistance of KIT D816V+ cells to TNF is mediated by the apoptosis-regulator BIRC5 (survivin). Expression of BIRC5 in neoplastic MC was confirmed by immunohistochemistry of SM patients. TNF serum levels are significantly elevated in SM patients and high TNF levels were identified as a biomarker associated with inferior survival. We here characterized TNF as a KIT D816V-dependent cytokine that promotes clonal dominance. We propose TNF and apoptosis-associated proteins as potential therapeutic targets in SM.

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