Chronic lymphocytic leukemia (CLL) is a heterogeneous disease without a 
well-defined genetic alteration responsible for the onset of the disease. 
Several lines of evidence coincide in identifying stimulatory and growth signals 
delivered by B-cell receptor (BCR), and co-receptors together with NFkB pathway, 
as being the driving force in B-cell survival in CLL. However, the molecular 
mechanism responsible for this activation has not been identified. Based on the 
hypothesis that BCR activation may depend on somatic mutations of the BCR and 
related pathways we have performed a complete mutational screening of 301 
selected genes associated with BCR signaling and related pathways using massive 
parallel sequencing technology in 10 CLL cases. Four mutated genes in coding 
regions (KRAS, SMARCA2, NFKBIE and PRKD3) have been confirmed by capillary 
sequencing. In conclusion, this study identifies new genes mutated in CLL, all 
of them in cases with progressive disease, and demonstrates that next-generation 
sequencing technologies applied to selected genes or pathways of interest are 
powerful tools for identifying novel mutational changes.