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. Here, LCK is linked to B-cell chronic lymphocytic leukemia.