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

点击翻译按钮获取中文摘要

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.