STAT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA

慢性淋巴细胞白血病(CLL)是最常见的白血病类型 在美国。然而，对分子的理解 这种疾病的基础缺乏反常现象。CLL是 以B淋巴细胞持续不受限制的生长为特征的。 因此，控制调节的信号通路中的缺陷 B淋巴细胞有丝分裂异常可能与其恶性程度有关。 B淋巴细胞的增殖通常受一种 分泌的细胞因子家族，通过与特定细胞结合而起作用 表面受体。一旦与它们的同源受体结合，大多数 细胞因子至少部分地通过激活一组转录来发出信号。 被称为统计数据的因素。统计数据可以在单个 酪氨酸残基，导致状态二聚体，核 易位、DNA结合和转录激活。在……里面 此外，几个STATS的功能受磷酸化的调节 在特定的丝氨酸残基上。这种额外的丝氨酸磷酸化 似乎对基因激活很重要，并可能用于整合 由不同的细胞内途径产生的信号。鉴于中央 STATS在调节B淋巴细胞生长和功能中的作用 我们考虑了统计数据中的异常情况 信号可能是存在缺陷的增长调控的基础， 慢性淋巴细胞性白血病恶性B淋巴细胞。我们最近报道，尽管 STATS的酪氨酸磷酸化在CLL中不存在，构成 特定丝氨酸残基Ser-727上STAT1和STAT3的磷酸化 在每种蛋白质中，都存在于所有人的外周血液中的B淋巴细胞中 到目前为止，CLL患者接受了检查，但没有检测到正常的B细胞。这个 目前的提案试图通过探索 这种磷酸化的机制及其在生物学中的后果 CLL.将追求四个具体目标：(1)分析 STAT1和STAT3丝氨酸磷酸化在基因调控中的作用 CLL细胞和正常淋巴细胞的激活和细胞存活； 确定抑制STAT酪氨酸磷酸化的作用 HAS对转化的B淋巴细胞生物学的影响；(3)分析 治疗慢性淋巴细胞性白血病的化疗药物氟达拉滨的疗效 (4)分离负责STAT信号转导的激酶(S)。 CLL细胞中STAT1和STAT3的Ser-727的磷酸化。结果 在这些实验中，我们计划辨别统计数据在 CLL细胞的异常生长，并寻找新的和 特定的疗法。

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.