Using microarrays, we further define a molecular signature of anergy in CLL cells consisting of the E3 ligases Cbl-b and Grail, the transcription factor Egr2 and the lymphocyte-specific protein kinase Lck. In addition, we define Lck as a direct target gene of NFAT2 in CLL cells and demonstrate that while the NFAT2-LCK axis is constitutively activated in indolent CLL, it is inactive in tumour cells from patients with aggressive CLL or Richter’s syndrome. This evidence concerns the gene EGR2 and Richter syndrome.