Deletion of a critical internalization domain in the G-CSFR in acute myelogenous leukemia preceded by severe congenital neutropenia
Deletion of a critical internalization domain in the G-CSFR in acute myelogenous leukemia preceded by severe congenital neutropenia
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DOI：
10.1182/blood.v93.2.440.402k23_440_446
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发表时间：
1999-01-15
期刊：
影响因子：
20.3
通讯作者：
Avalos, BR
中科院分区：
文献类型：
--
作者：
Hunter, MG;Avalos, BR
粒细胞集落刺激因子受体（G-CSFR）的获得性突变发生在发展为急性髓性白血病（AML）的严重先天性中性粒细胞减少症（SCN）患者亚群中。这些突变影响一个等位基因，导致对G-CSF的超增殖反应，可能是通过显性-阴性机制。本研究表明，在SCN/AML患者的G-CSFR突变体中，介导配体内化的G-CSFR关键结构域被删除。该结构域的缺失导致配体内化受损、受体下调缺陷和生长信号增强。这些结果解释了G-CSFR突变在SCN/AML中显性阴性表型和对G-CSF超敏的发病机制中的分子基础。(C) 1999年由美国血液病学会出版。
Acquired mutations in the granulocyte colony-stimulating factor receptor (G-CSFR) occur in a subset of patients with severe congenital neutropenia (SCN) who develop acute myelogenous leukemia (AML). These mutations affect one allele and result in hyperproliferative responses to G-CSF, presumably through a dominant-negative mechanism. Here we show that a critical domain in the G-CSFR that mediates (ligand internalization is deleted in mutant G-CSFR forms from patients with SCN/AML. Deletion of this domain results in impaired ligand internalization, defective receptor downmodulation, and enhanced growth signaling. These results explain the molecular basis for G-CSFR mutations in the pathogenesis of the dominant-negative phenotype and hypersensitivity to G-CSF in SCN/AML. (C) 1999 by The American Society of Hematology.