The usage of the subset 8 configuration in the B cell receptor (BCR), which has been reported to have an association to NOTCH1 somatic mutations and which shows an unlimited propensity to autonomous BCR signaling and to respond to multiple auto-antigens and immune stimuli from the microenvironment, may explain the particular aggressiveness of CLL harboring subset 8 BCR and their increased propensity to transform into RS [10, 18]. Here, NOTCH1 is linked to B-cell chronic lymphocytic leukemia.