Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype

作者：Chan Eunice Ching; Bai Yun; Kirshenbaum Arnold S; Fischer Elizabeth R; Simakova Olga; Bandara Geethani; Scott Linda M; Wisch Laura B; Cantave Daly; Carter Melody C; Lewis John C; Noel Pierre; Maric Irina; Gilfillan Alasdair M; Metcalfe Dean D; Wilson Todd M^*

来源：Journal of Allergy and Clinical Immunology, 2014, 134(1): 178-+.

DOI：10.1016/j.jaci.2013.12.1090

• KIT
• K509I
• mastocytosis
• germline
• mast cells
• well differentiated

Background: Mastocytosis associated with germline KIT activating mutations is exceedingly rare. We report the unique clinicopathologic features of a patient with systemic mastocytosis caused by a de novo germline KIT K509I mutation.
Objectives: We sought to investigate the effect of the germline KIT K509I 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 the KIT K509I mutation was established.
Results: KIT K509I biopsied mast cells were round, CD25(-), and well differentiated. KIT K509I 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. KIT K509I 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 of KIT at the adjacent exonic junction.
Conclusion: Germline KIT mutations associated with mastocytosis drive a well-differentiated mast cell phenotype distinct to that of somatic KIT D816V disease, the oncogenic potential of which might be influenced by SCF and selective KIT splicing.

• 出版日期2014-7