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

慢性淋巴细胞白血病(CLL)是成人最常见的白血病。它是一种以CD19、CD5和CD23表达为特征的成熟B细胞紊乱。大多数CLL患者表现出无痛的临床病程，这通常与他们的白血病细胞无能表型有关，涉及对B细胞受体刺激的无反应状态。这类患者通常不需要长时间的治疗。高达10%的CLL患者在他们的病程中发展为侵袭性B细胞淋巴瘤(里希特综合征)，这与悲惨的预后有关。在完成的资助期，我们可以证明NFAT2是CLL无能表型的关键调节因子。B细胞特异性的NFAT2消融导致TCL1转基因小鼠模型中无能表型的丧失，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。利用基因表达分析，我们可以进一步定义由Cbl-b、Grail、Egr2和Lck组成的无能信号。我们还可以证明NFAT2-LCK信号轴在侵袭性慢性淋巴细胞性白血病和里氏S综合征患者中完全失活。在即将到来的资助期间，我们计划调查我们的无能基因签名在不同预后组的人类CLL患者中的临床相关性。我们进一步计划通过焦磷酸测序详细分析NFAT2启动子的甲基化特征，来描述侵袭性CLL和里氏S综合征中NFAT2抑制的机制。NFAT2靶基因Lck在CLL发病机制和无能表型调节中的功能作用将在TCL1小鼠模型中详细阐述。

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.