IDENTIFICATION OF A POINT MUTATION IN THE CATALYTIC DOMAIN OF THE PROTOONCOGENE C-KIT IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS OF PATIENTS WHO HAVE MASTOCYTOSIS WITH AN ASSOCIATED HEMATOLOGIC DISORDER
IDENTIFICATION OF A POINT MUTATION IN THE CATALYTIC DOMAIN OF THE PROTOONCOGENE C-KIT IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS OF PATIENTS WHO HAVE MASTOCYTOSIS WITH AN ASSOCIATED HEMATOLOGIC DISORDER
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DOI：
10.1073/pnas.92.23.10560
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发表时间：
1995-11-07
影响因子：
11.1
通讯作者：
METCALFE, DD
中科院分区：
文献类型：
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作者：
NAGATA, H;WOROBEC, AS;METCALFE, DD
干细胞和肥大细胞都表达c-kif，并在暴露于c-kit配体后增殖。c-kit基因突变可增强或干扰c-kit受体启动导致细胞增殖的细胞内途径的能力。这些观察结果提示我们肥大细胞增多症可能是由c-kif基因突变引起的。从惰性肥大细胞增多症、肥大细胞增多症伴相关血液病、侵袭性肥大细胞增多症、孤立性肥大细胞瘤和与肥大细胞增多症无关的慢性粒单核细胞白血病患者的外周血单核细胞合成的cDNA因此筛选c-kit突变。该分析显示，4例伴有以骨髓增生异常特征为主的相关血液病的肥大细胞增多症患者中，4例在c-kit mRNA的nt 2368处发生A -> T置换，导致Asp-816 ->瓦尔置换。一名患有肥大细胞增多症并伴有血液系统疾病的患者在基因组DNA中有相应的突变。肥大细胞系中相同或相似的氨基酸取代导致c-kit受体的配体非依赖性自磷酸化。在其他疾病类别的患者或67名对照中的67名中未发现这种突变。在伴有相关血液疾病的肥大细胞增多症患者中发现c-kit中Asp 816 Val点突变，不仅可以深入了解这种形式的肥大细胞增多症的发病机制，而且还可以了解造血功能可能变得失调，并可能有助于提供一种确认诊断、评估预后和制定干预策略的方法。
Both stem cells and mast cells express c-kif and proliferate after exposure to c-kit ligand. Mutations in c-kit may enhance or interfere with the ability of c-kit receptor to initiate the intracellular pathways resulting in cell proliferation. These observations suggested to us that mastocytosis might in some patients result from mutations in c-kif. cDNA synthesized from peripheral blood mononuclear cells of patients with indolent mastocytosis, mastocytosis with an associated hematologic disorder, aggressive mastocytosis, solitary mastocytoma, and chronic myelomonocytic leukemia unassociated with mastocytosis was thus screened for a mutation of c-kit. This analysis revealed that four of four mastocytosis patients with an associated hematologic disorder with predominantly myelodysplastic features had an A --> T substitution at nt 2368 of c-kit mRNA that causes an Asp-816 --> Val substitution. One of one patient examined who had mastocytosis with an associated hematologic disorder had the corresponding mutation in genomic DNA. Identical or similar amino acid substitutions in mast cell lines result in ligand-independent autophosphorylation of the c-kit receptor. This mutation was not identified in the patients within the other disease categories or in 67 of 67 controls. The identification of the point mutation Asp816Val in c-kit in patients with mastocytosis with an associated hematologic disorder provides insight not only into the pathogenesis of this form of mastocytosis but also into how hematopoiesis may become dysregulated and may serve to provide a means of confirming the diagnosis, assessing prognosis, and developing intervention strategies.