Pathogenesis/Diagnosis/Therapy Of Systemic Mast Cell Dis

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Abstract

Activating mutations in the c-kit protooncogene codon 816 are found in most patients with systemic mastocytosis involving the bone marrow. The D816V c-kit mutation found in mast cells of patients with systemic mastocytosis was used as a trackable genetic marker to assess the lineage relationship between mast cells and basophils. Basophils carrying the D816V mutation in mastocytosis were detected only in the context of multilineage involvement, arguing against the presence of a bi-lineage-restricted committed progenitor for mast cells and basophils. Mastocytosis is characterized by the presence of heterotypic cluster of mast cells and lymphocytes in bone marrow samples. In order to assess whether clonal proliferation is the basis for this clustering, laser capture microdissection was used to examine B cells, T cells and mast cells from both lesional and non-lesional areas of biopsies. While the D816V c-kit mutation was detected in mast cells, and B and T cells from lesional but not from non-lesional areas of the marrow, clonality studies demonstrated that the B cell population was oligoclonal, arguing against clonal proliferation as the cause for clustering. Among cytokines, only IL6 has been reported to be increased in the plasma of patients with mastocytosis. In order to investigate the clinical significance of this observation, plasma IL6 levels were correlated with multiple disease parameters in 29 patients with mastocytosis. IL6 levels were found to predict disease variant and extent of organ involvement in patients with mastocytosis, suggesting that it may be a useful surrogate marker of disease severity and may contribute to disease pathogenesis.