Transformation via “canonical hits” vs “pathway tweaking.” (A) Schematic depiction of a generic pathway and possible levels of “oncogenic” lesions: “membrane level” includes extracellular signals, both from the microenvironment (including BCR signaling) or via autocrine stimulation, as well as mutations in receptors; “signaling levels 1 and 2” simplify different levels of action in a single pathway; “nuclear controls” mean transcription factor changes; and “global controls” mean changes in micro RNA, epigenetics, splicing machinery, or DNA damage response. (B) Model of classic oncogene transformation (1 strong and highly recurrent driver leads to clonal expansion). Of course, this is a gross simplification, whereas in reality, there are collaborating lesions in all these instances. (C) Multiple ways of transformation in CLL by activation with or without mutation, and on multiple levels of a defined set of collaborating pathways. Professional illustration by XavierStudio.