Role of the Ca2+/NFAT signalling pathway in the pathogenesis of chronic lymphocytic leukemia (CLL)

Ca2/NFAT信号通路在慢性淋巴细胞白血病（CLL）发病机制中的作用

• 批准号: 213120007
• 负责人: Privatdozent Dr. Martin Müller
• 金额: --
• 依托单位: KRH Klinikum Siloah
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/213120007?language=en
• 关键词: Role; Ca2+; NFAT; signalling; pathway

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. It is a disorder of mature B cells characterized by the expression of CD19, CD5 and CD23. A majority of CLL patients exhibits an indolent clinical course which is usually associated with an anergic phenotype of their leukemia cells refering to a state of unresponsiveness to B cell receptor stimulation. Patients of this group normally do not require treatment for long periods of time. Up to 10% of CLL patients develop a transformation to aggressive B cell lymphoma during their disease course (Richter syndrome), which is associated with a dismal prognosis. In the completed funding period we could demonstrate that NFAT2 is a critical regulator of the anergic phenotype in CLL. B cell-specific ablation of NFAT2 results in the loss of the anergic phenotype in the TCL1 transgenic mouse model culminating in a significantly reduced life expectancy and transformation into aggressive B cell lymphoma. Using gene expression analysis we could further define an anergy signature consisting of Cbl-b, Grail, Egr2 and Lck. We could also show that the NFAT2-LCK signaling axis is completely inactivated in patients with aggressive CLL and Richter´s syndrome. In the upcoming funding period we plan to investigate the clinical relevance of our anergy gene signature in human CLL patients from different prognostic groups. We further plan to delineate the mechanism of NFAT2 suppression in aggressive CLL and in Richter´s syndrome by detailed analysis of the methylation profile of the NFAT2 promoter using pyrosequencing. The functional role of the NFAT2 target gene Lck in the pathogenesis of CLL and in the regulation of the anergic phenotype will be addressed in detail in the TCL1 mouse model.

慢性淋巴细胞白血病（CLL）是成人中最常见的白血病。它是一种成熟B细胞的疾病，其特征在于表达CD 19、CD 5和CD 23。大多数CLL患者表现出惰性的临床过程，这通常与他们的白血病细胞的无反应性表型相关，从而进入对B细胞受体刺激无反应的状态。这类患者通常不需要长期治疗。高达10%的CLL患者在其病程期间发展为侵袭性B细胞淋巴瘤（Richter综合征），这与令人沮丧的预后相关。 在完成的资助期内，我们可以证明NFAT 2是CLL中无反应性表型的关键调节因子。NFAT 2的B细胞特异性消融导致TCL 1转基因小鼠模型失去无能表型，最终导致预期寿命显着降低并转化为侵袭性B细胞淋巴瘤。使用基因表达分析，我们可以进一步定义由Cbl-b、Grail、Egr 2和Lck组成的无反应性特征。我们还可以证明NFAT 2-LCK信号轴在侵袭性CLL和Richter综合征患者中完全失活。在即将到来的资助期内，我们计划研究我们的无反应性基因签名在来自不同预后组的人类CLL患者中的临床相关性。我们计划通过焦磷酸测序对NFAT 2启动子的甲基化谱进行详细分析，进一步阐明NFAT 2在侵袭性CLL和Richter综合征中的抑制机制。NFAT 2靶基因Lck在CLL发病机制和无反应性表型调节中的功能作用将在TCL 1小鼠模型中详细讨论。