STAT3 AND G-CSF MEDIATED MYELOID DIFFERENTIATION

尽管有较新的治疗方式，AML的总体死亡率仍 超过50%。 分化剂已经显示出希望，但由于 由于缺乏疗效和毒性，我们仍在寻找额外的或 更好的代理商 在最初的研究中，G-CSF可以覆盖 白血病细胞系和一些新鲜AML中的分化阻滞 细胞 然而，大多数反应性AML细胞增殖， 在暴露于G-CSF后的分化。 根据我们最近的研究， 假设在AML细胞中，Stat 3 α激活可能干扰 G-CSF驱动的分化信号。 在这份提案中，我们计划 确定1）G-CSF驱动的骨髓细胞是否需要Stat 3 分化，以及2）Stat 3相对水平改变的影响 同种型Stat 3 α和Stat 3 β对G-CSF驱动的髓样细胞 分化通过Stat 3的反义抑制和 一个占主导地位的负面Stat 3，我们将确认Stat 3的作用， 骨髓生成 然后通过过表达Stat 3alpha，我们将检查 相对Stat 3亚型水平在G-CSF驱动的骨髓生成中的作用。 的 该项目的长期目标是应用从这些信息中获得的信息， 研究设计新的分化诱导剂， AML的治疗。 这种疗法可能将Stat 3 alpha靶向于 它在AML细胞中的激活或表达。

Despite newer treatment modalities, overall mortality from AML still exceeds 50 percent. Differentiation agents have shown promise but due to lack of efficacy and toxicity we are still looking for additional or better agents. In the initial studies, G-CSF could override the differentiation block in leukemic cell lines and in some fresh AML cells. However, most responsive AML cells proliferated without differentiation upon exposure to G-CSF. Based on our recent studies we postulate that in AML cells, Stat3alpha activation may interfere with the G-CSF-driven differentiation signal. In this proposal, we plan to determine 1) if Stat3 is required for G-CSF-driven myeloid differentiation, and 2) the effect of altered relative levels of Stat3 isoforms Stat3alpha and Stat3beta on G-CSF-driven myeloid differentiation. By meals of antisense inhibition of Stat3 and use of a dominant negative of Stat3, we shall confirm the role of Stat3 in myelopoiesis. Then by overexpressing Stat3alpha, we shall examine the role of relative Stat3 isoforms level in G-CSF-driven myelopoiesis. The long-term goal of this project is to apply information gained from these studies to the design of new differentiation-inducing agents for the treatment of AML. Such therapies might target Stat3alpha at the level of its activation or expression in AML cells.