CYTOKINE SIGNALING IN MYELOID LEUKEMIAS

描述：(改编自申请人的摘要)本申请旨在 描述增殖信号通路中的关键步骤 在原始髓系细胞中被GM-CSF激活的相关细胞因子。在… 至少部分髓系白血病可能是由于过度活动所致 这样的信号通路。确定以下方面的关键步骤或唯一步骤 这样的级联可能允许开发药物干预措施来 特别是破坏了这些通路。这一点的具体假设 应用是Pim-1基因工程的表达，全长33kd 丝氨酸/苏氨酸激酶是有效增殖所必需的 通过粒-巨噬细胞集落刺激因子及相关受体传递信号。申请人还进一步 假设Pim-1的表达作为一种特定的指标 激活这些通路。这一假设将由 构建允许过度表达或阻断的细胞系统 Pim-1的活性。依赖因子的髓系细胞株将是 用质粒构建体或逆转录病毒构建体转染以允许 Pim-1基因产物的自主表达。这些株系将 接受不依赖因素的生长、分化障碍、 抑制细胞凋亡和同型聚集。相似的细胞系 将利用含有反义Pim-1结构的质粒来产生 抑制内源性Pim-1基因的活性。这些细胞将是 人粒-巨噬细胞集落刺激因子及其相关细胞因子的反应性研究 有分化的倾向。

DESCRIPTION: (Adapted from applicant's abstract)This application seeks to characterize critical steps in the proliferative signalling pathways activated by GM-CSF in related cytokines in primitive myeloid cells. At least some cases of myeloid leukemia likely result from over activity of such signal pathways. Identification of critical or unique steps in such cascades may allow development of pharmacologic interventions to specifically disrupt these pathways. The specific hypothesis of this application is that expression of the pim-1 gene project, a 33 kd serine/threonine kinase, is necessary for effective proliferative signalling through GM-CSF and related receptors. The applicant further hypothesizes that pim-1 expression serves as a specific indicator of activation of such pathways. The hypothesis will be investigated by constructing cell systems which allow for the over expression or blockade of pim-1 activity. Factor-dependent myeloid cell lines will be transfected with plasmid constructs or retroviral constructs to allow autonomous expression of the pim-1 gene product.These lines will then be examined for factor- independent growth, impaired differentiation, inhibition of apoptosis and homotypic aggregation. Similar cell lines will be created utilizing plasmids containing antisense pim-1 constructs to inhibit activity of the endogenous pim-1 gene. These cells will be studied for the responsiveness to GM-CSF and related cytokines and their propensity to differentiation.