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: 6626615
• 负责人: DAVID A. FRANK
• 金额: $ 27.23万
• 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 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626615
• 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

项目成果

SCF and G-CSF lead to the synergistic induction of proliferation and gene expression through complementary signaling pathways.

• DOI: 10.1182/blood.v96.10.3422.h8003422_3422_3430
• 发表时间: 2000-11
• 期刊: Blood
• 影响因子: 20.3
• 作者: Rafael F Duarte;D. Frank

In vivo activation of signal transducer and activator of transcription 1 after CD154 gene therapy for chronic lymphocytic leukemia is associated with clinical and immunologic response.

慢性淋巴细胞白血病 CD154 基因治疗后信号转导器和转录激活剂 1 的体内激活与临床和免疫反应相关。

• 发表时间: 2003
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research.
• 作者: Battle,TraciE;Wierda,WilliamG;Rassenti,LauraZ;Zahrieh,David;Neuberg,Donna;Kipps,ThomasJ;Frank,DavidA
• 通讯作者: Frank,DavidA