G-CSFR MUTATIONS--A NOVEL MECHANISM OF LEUKEMOGENESIS

描述：（改编自研究者的摘要）遗传病变

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.