STAT3 AND G-CSF MEDIATED MYELOID DIFFERENTIATION

尽管治疗方式较新，但急性髓系白血病的总死亡率仍然 超过50%。差异化代理已经显示出希望，但也应该 由于缺乏有效性和毒性，我们仍在寻找额外的或 更好的特工。在最初的研究中，G-CSF可以超越 白血病细胞系和某些新鲜AML中的分化障碍 细胞。然而，大多数有反应的AML细胞在没有 在G-CSF作用下发生分化。根据我们最近的研究，我们 假设在AML细胞中，Stat3pha的激活可能会干扰 G-CSF驱动的分化信号。在这项提案中，我们计划 确定1)G-CSF驱动的髓系细胞是否需要STAT3 分化，以及2)STAT3相对水平改变的影响 粒细胞集落刺激因子驱动的髓系细胞中的Stat3α和Stat3β亚型 差异化。通过反义抑制STAT3的用餐和使用 作为STAT3的显性阴性，我们将确认STAT3在 骨髓再生。然后，通过过度表达Stat3pha，我们将检查 相对STAT3亚型水平在G-CSF诱导的骨髓生成中的作用这个 该项目的长期目标是将从这些项目中获得的信息 新型细胞分化诱导剂的设计研究 急性髓系白血病的治疗。这类疗法可能针对Stat3pha水平 其在急性髓系白血病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.