Akin Cem, Fumo Gerard, Yavuz Akif S, Lipsky Peter E, Neckers Len, Metcalfe Dean D
Laboratory of Allergic Diseases, National Instititute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Blood. 2004 Apr 15;103(8):3222-5. doi: 10.1182/blood-2003-11-3816. Epub 2003 Dec 24.
Mutational analysis of the c-kit gene in a patient with a previously undescribed variant of mast cell disease revealed a germline mutation, Phe522Cys, within the transmembrane portion of the Kit receptor protein. Transfection experiments revealed that the mutation caused ligand-independent autophosphorylation of Kit, which was inhibited by the tyrosine kinase inhibitor imatinib mesylate. The patient's bone marrow biopsy and aspirate displayed unique pathologic features with the presence of excessive numbers of mature-appearing mast cells and absence of aberrant mast cell surface expression of CD2, CD25, and CD35. Therapy with imatinib mesylate resulted in a dramatic improvement in mast cell burden and clinical symptoms. These results highlight the significance of the transmembrane region of Kit in activation of the molecule and its importance in mast cell development and suggest a role for screening for transmembrane c-kit mutations in patients with mastocytosis in association with the decision to use imatinib mesylate.
对一名患有此前未描述过的肥大细胞疾病变体的患者进行的c-kit基因的突变分析显示，在Kit受体蛋白的跨膜部分存在一个种系突变，即Phe522Cys。转染实验表明，该突变导致Kit的配体非依赖性自磷酸化，而甲磺酸伊马替尼可抑制这种自磷酸化。患者的骨髓活检和穿刺显示出独特的病理特征，存在大量外观成熟的肥大细胞，且不存在CD2、CD25和CD35的异常肥大细胞表面表达。甲磺酸伊马替尼治疗使肥大细胞负荷和临床症状得到显著改善。这些结果突出了Kit跨膜区域在分子激活中的重要性及其在肥大细胞发育中的重要性，并提示在肥大细胞增多症患者中筛查跨膜c-kit突变对于决定使用甲磺酸伊马替尼具有一定作用。
