STAT3 AND G-CSF MEDIATED MYELOID DIFFERENTIATION

STAT3 和 G-CSF 介导的骨髓分化

• 批准号: 6439430
• 负责人: ARUP CHAKRABORTY
• 金额: $ 4.09万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6439430
• 关键词: DNA binding protein; JAK kinase; acute myelogenous leukemia; antisense nucleic acid; biological signal transduction; cell differentiation; clone cells; colony stimulating factor; enzyme activity; enzyme inhibitors; gene expression; growth factor receptors; isozymes; mitogen activated protein kinase; myeloid stem cell; neoplastic cell; oligonucleotides; pathologic process; phenotype; transfection /expression vector

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.

尽管采用了新的治疗方式，但 AML 的总体死亡率仍然很高 超过50%。 分化剂已显示出希望，但由于 由于缺乏功效和毒性，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 可以推翻 白血病细胞系和某些新鲜 AML 中的分化受阻 细胞。 然而，大多数有反应的 AML 细胞在没有 暴露于 G-CSF 后的分化。 根据我们最近的研究，我们 假设在 AML 细胞中，Stat3alpha 激活可能会干扰 G-CSF驱动的分化信号。 在本提案中，我们计划 确定 1) G-CSF 驱动的骨髓细胞是否需要 Stat3 分化，以及 2) Stat3 相对水平改变的影响 G-CSF 驱动的骨髓细胞中的亚型 Stat3alpha 和 Stat3beta 差异化。通过 Stat3 的反义抑制和使用 Stat3 的显性阴性，我们将确认 Stat3 在 骨髓生成。 然后通过过度表达 Stat3alpha，我们将检查 相对 Stat3 同种型水平在 G-CSF 驱动的骨髓细胞生成中的作用。 这 该项目的长期目标是应用从这些项目中获得的信息 研究设计新的分化诱导剂 AML 的治疗。 此类疗法可能以 Stat3alpha 水平为目标 其在 AML 细胞中的激活或表达。