NOTCH1 mutations were the first molecular lesion identified through massive parallel next generation sequencing in CLL by two independent groups.10,11NOTCH1 mutations are significantly more frequent in CLL with unmutated, rather than mutated, immunoglobulin genes, are significantly enriched in CLL harboring trisomy 12, and identify a distinct clinico-molecular subgroup of CLL with deregulated cell cycle and short survival.10–12,14,16,51–53. This evidence concerns the gene NOTCH1 and B-cell chronic lymphocytic leukemia.