Affected genes in CLL discovered through genomic sequencing studies can be grouped into seven core cellular pathways. Genes recurrently mutated in CLL samples are shown in red ovals, while genes found to be mutated in isolated samples but which did not reach statistical significance are shown as pink ovals. Affected cellular elements include four signaling pathways with a known role in B-cell biology: inflammatory pathways, B-cell receptor signaling, Notch signaling, and Wnt signaling. Notch and Wnt signaling both provide important pro-survival input for CLL cells, allowing them to evade apoptosis [115–117]. In addition, they serve as an important bridge with the microenvironment, which is of particular importance in CLL, as manifested by relatively poor cell survival outside of the endogenous niche (for example, in in vitro or in vivo animal models) . BCR signaling and inflammatory pathways may serve similar functions, and in addition may form optimal early targets for somatic mutations as they hijack physiologically active cellular pathways in relatively differentiated B cells [75, 119]. In addition, three intranuclear processes are involved, including DNA repair, chromatic modification and RNA processing. Although the role of DNA repair disruptions has been extensively investigated, with multiple effects on pro-survival circuits, growth and genetic plasticity [120, 121], the role of the other two intranuclear processes remains to be fully elucidated in CLL. IC, intracellular; C, cytoplasm.