Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival
Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival
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DOI：
10.1182/blood.v95.6.2132
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发表时间：
2000-03-15
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
严重先天性中性粒细胞减少症（SCN）患者发展为急性髓性白血病（AML）的风险增加。在进展为AML的SCN患者亚群中，已检测到粒细胞集落刺激因子（G-CSF）受体的获得性突变，导致G-CSF受体（G-CSFR）蛋白的截短形式表达。在本文中，我们发现从SCN/AML患者中最常见的G-CSFR突变形式（Delta 716）通过涉及AM （pi3激酶的下游靶点）的机制赋予细胞凋亡抗性并延长细胞存活。G-CSF刺激表达G-CSFR截断突变体的细胞可诱导Akt的持续激活和促凋亡蛋白Bad的延长磷酸化，从而提高细胞存活率。细胞存活的延长允许有足够的时间获得额外的致癌事件，这可能是G-CSFR突变促进白血病发生的重要机制，这些数据为G-CSFR突变对AML的病理生理贡献提供了进一步的见解，(C) 2000年由美国血液学会发表。
patients with severe congenital neutropenia (SCN) are at increased risk for the development of acute myelogenous leukemia (AML), In the subset of patients with SCN that progresses to AML, acquired mutations in the receptor for granulocyte colony-stimulating factor (G-CSF) have been detected that result in the expression of truncated forms of the G-CSF receptor (G-CSFR) protein. G-CSFR truncation mutants from these patients transduce hyperproliferative growth responses, In this paper, we show that the most frequently isolated mutant G-CSFR form from patients with SCN/AML (Delta 716) confers resistance to apoptosis and prolongs cell survival through a mechanism involving AM, a downstream target of PI3-kinase. G-CSF stimulation of cells expressing the G-CSFR truncation mutant induces sustained activation of Akt and prolonged phosphorylation of the pro-apoptotic protein Bad, resulting in enhanced cell survival. Extension of cell survival allowing for sufficient time for the acquisition of additional oncogenic events may represent an important mechanism by which G-CSFR mutations contribute to leukemogenesis, These data provide further insight Into the pathophysiologic contribution of G-CSFR mutations to AML, (C) 2000 by The American Society of Hematology.