STAT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA

慢性淋巴细胞白血病中的 STAT 信号转导

• 批准号: 6342108
• 负责人: DAVID A. FRANK
• 金额: $ 25.67万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-07 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342108
• 关键词: B lymphocyte; DNA binding protein; SDS polyacrylamide gel electrophoresis; biological signal transduction; cell growth regulation; chronic lymphocytic leukemia; clinical research; cytogenetics; cytokine; drug adverse effect; flow cytometry; fludarabine; gel mobility shift assay; gene expression; gene induction /repression; human subject; immunocytochemistry; immunoprecipitation; leukocyte activation /transformation; molecular cloning; neoplastic growth; phosphorylation; protein tyrosine kinase; tissue /cell culture; transcription factor; western blottings

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. However, an understanding of the molecular abnormalities which underlie this disease is lacking. CLL is characterized by the continuous unrestrained growth of B lymphocytes. As such, a defect in a signaling pathway that controls the regulation of mitosis in B lymphocytes might be responsible for this malignancy. The proliferation of B lymphocytes is normally closely regulated by a family of secreted cytokines which act by binding to specific cell surface receptors. Upon binding to their cognate receptor, most cytokines signal, at least in part, by activating a set of transcription factors known as STATs. STATs can be phosphorylated on a single tyrosine residue, which leads to STAT dimerization, nuclear translocation, DNA binding, and transcriptional activation. In addition, the function of several STATs is modulated by phosphorylation on specific serine residues. This additional serine phosphorylation appears to be important for gene activation, and may serve to integrate signals generated by diverse intracellular pathways. Given the central role of STATs in modulating the growth and function of B lymphocytes, we considered the possibility that abnormalities in STAT-mediated signaling might underlie the defective growth regulation seen in the malignant B lymphocytes of CLL. We have recently reported that although tyrosine phosphorylation of STATs is not present in CLL, constitutive phosphorylation of STAT1 and STAT3 on specific serine residues, ser-727 in each protein, is found in the peripheral blood B lymphocytes of all patients with CLL examined thus far, but not in normal B cells. The present proposal seeks to extend these findings by exploring the mechanism of this phosphorylation and its consequence in the biology of CLL. Four specific aims will be pursued: (1) To analyze the effect that serine phosphorylation of STAT1 and STAT3 plays in mediating gene activation and cell survival in CLL cells and normal lymphocytes; (2) To determine the effect that inhibition of STAT tyrosine phosphorylation has on the biology of transformed B lymphocytes; (3) To analyze the effect that a chemotherapeutic drug used to treat CLL, fludarabine, has on STAT signaling; and (4) To isolate the kinase(s) responsible for the phosphorylation of ser-727 of STAT1 and STAT3 in CLL cells. As a result of these experiments, we plan to discern the role of STATs in the abnormal growth of CLL cells, and to identify targets for novel and specific therapies.

慢性淋巴细胞白血病（CLL）是最常见的白血病形式 在美国 然而，对分子的理解 这种疾病背后的异常是缺乏的。CLL是 以B淋巴细胞的连续无限制生长为特征。 因此，控制调节的信号通路中的缺陷 B淋巴细胞的有丝分裂异常可能是导致这种恶性肿瘤的原因。 B淋巴细胞的增殖通常由一种 通过与特定细胞结合而起作用的分泌性细胞因子家族 表面受体 在与其同源受体结合后，大多数 细胞因子至少部分地通过激活一组转录来传递信号， 这些因素被称为STAT。 STAT可以在单个 酪氨酸残基，导致STAT二聚化，核 易位、DNA结合和转录激活。 在 此外，几种STAT的功能通过磷酸化调节 在特定的丝氨酸残基上。 这种额外的丝氨酸磷酸化 似乎是重要的基因激活，并可能有助于整合 由多种细胞内途径产生的信号。 鉴于中央 STAT在调节B淋巴细胞的生长和功能中的作用， 我们考虑了STAT介导的异常 信号传导可能是生长调节缺陷的基础， CLL的恶性B淋巴细胞。 我们最近报道说，虽然 STAT的酪氨酸磷酸化不存在于CLL中，组成型 STAT 1和STAT 3在特定丝氨酸残基上的磷酸化，ser-727 在每种蛋白质中，都存在于所有人的外周血B淋巴细胞中。 CLL患者中，但不是在正常B细胞中。 的 本提案旨在通过探索 这种磷酸化的机制及其在生物学中的后果 CLL。 具体目标有四：（1）分析 STAT 1和STAT 3的丝氨酸磷酸化在介导基因 CLL细胞和正常淋巴细胞中的活化和细胞存活;（2） 为了确定抑制STAT酪氨酸磷酸化的作用， 对转化B淋巴细胞生物学特性的影响; 用于治疗CLL的化疗药物氟达拉滨 （4）分离负责STAT信号传导的激酶， 在CLL细胞中STAT 1和STAT 3的Ser-727磷酸化。因此 在这些实验中，我们计划辨别STAT在 CLL细胞的异常生长，并确定新的和 具体治疗。