G-CSFR MUTATIONS--A NOVEL MECHANISM OF LEUKEMOGENESIS

描述：(改编自研究者的摘要)遗传性损伤 涉及越来越多的癌基因已被认识到在 在人类白血病发展过程中的作用。这些损伤导致 基因正常功能的破坏或其不适当的 表情。大多数已被研究的癌基因在急性白血病中 骨髓性白血病(AML)编码的蛋白质功能是 细胞内信号分子或作为转录因子，并发挥作用 在调节细胞增殖、分化和存活中的作用。 粒细胞集落刺激因子受体基因突变 基因最近在急性髓系白血病患者中被报道，并提供了第一个 细胞因子受体异常与临床急性髓系白血病的关系这些突变 这导致G-CSFR的羧基末端区域被截断 干扰正常野生型G-CSFR的成熟信号功能 通过显性-负性导致对G-CSF的过度增殖反应 机制。这种损害代表了一种新的白血病发生机制。 急性髓系白血病患者G-CSFR基因突变频率为 目前情况不明。同样，人们对这种机制知之甚少。 促进显性-负性表型或信号通路 突变型G-CSFR介导对G-CSF的增强生长反应 急性髓系白血病患者。这里建议进行实验，以便更好地了解 与G-CSFR和生长调节相关的信号事件 G-CSFR基因突变导致细胞失控的机制 扩散。还将进行研究，以确定 急性髓系白血病患者G-CSFR基因突变的研究这一信息将澄清 G-CSFR突变在急性髓系白血病发病机制中的作用 制定合理的G-CSF临床应用指南 并可能为急性髓细胞白血病提供潜在的新的治疗靶点 急性髓系白血病的治疗。

DESCRIPTION: (adapted from the investigator's abstract) Genetic lesions involving an increasing number of oncogenes have been recognized to play a role in the development of human leukemias. These lesions result in disruption of the normal function of genes or in their inappropriate expression. Most of the oncogenes which have been studied in acute myelogenous leukemia (AML) encode proteins that function either as intracellular signaling molecules or as transcription factors, and play a role in the regulation of cell proliferation, differentiation, and survival. Mutations of the granulocyte colony-stimulating factor receptor (G-CSFR) gene have recently been reported in patients with AML and provide the first link between abnormal cytokine receptors and clinical AML. These mutations which result in truncations of the carboxy-terminal region of the G-CSFR disrupt the maturation signaling function of the normal wild-type G-CSFR and lead to hyperproliferative responses to G-CSF through a dominant-negative mechanism. Such lesions represent a novel mechanism of leukemogenesis. The frequency of mutations in the G-CSFR gene in patients with AML is at present unknown. Likewise, little is known about the mechanisms that promote the dominant-negative phenotype or the signaling pathways that mediate enhanced growth responses to G-CSF by mutant G-CSFR forms from patients with AML. Experiments are proposed here to better understand the signaling events associated with growth regulation by the G-CSFR and the mechanisms by which mutations in the G-CSFR gene result in unregulated cell proliferation. Studies will also be done to determine the frequency of G-CSFR mutations in patients with AML. This information will clarify the role of G-CSFR mutations in the pathogenesis of AML, permit the formulation of rational guidelines for appropriate clinical use of G-CSF in patients with AML, and may reveal potential novel therapeutic targets for the treatment of AML.