Mastocytosis associated with a rare germlineKITK509I mutation displays a well-differentiated mast cell phenotype

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Background:Mastocytosis associated with germlineKITactivating mutations is exceedingly rare. We report the unique clinicopathologic features of a patient with systemic mastocytosis caused by ade novogermlineKITK509I mutation.Objectives:We sought to investigate the effect of the germlineKITK509I mutation on human mast cell development and function.Methods:Primary human mast cells derived from CD34+ peripheral blood progenitors were examined for growth, development, survival, and IgE-mediated activation. In addition, a mast cell transduction system that stably expressed theKITK509I mutation was established.Results:KITK509I biopsied mast cells were round, CD25, and well differentiated.KITK509I progenitors cultured in stem cell factor (SCF) demonstrated a 10-fold expansion compared with progenitors from healthy subjects and developed into mature hypergranular mast cells with enhanced antigen-mediated degranulation.KITK509I progenitors cultured in the absence of SCF survived but lacked expansion and developed into hypogranular mast cells. A KIT K509I mast cell transduction system revealed SCF-independent survival to be reliant on the preferential splicing ofKITat the adjacent exonic junction.Conclusion:GermlineKITmutations associated with mastocytosis drive a well-differentiated mast cell phenotype distinct to that of somaticKITD816V disease, the oncogenic potential of which might be influenced by SCF and selectiveKITsplicing.

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