A highly simplified model of the natural history of CML. (a) The CML leukemia stem cell (blue) regenerates, but also gives rise to leukemia progenitors. Presumably early in the disease, most are sensitive to TKI. With time and unopposed Bcr-Abl activity, cells arise with mutations and/or genetic features of progression. The latter eventually have a greater proliferative edge, and progression to blast crisis occurs. (b) If a TKI is initiated early in disease, before genetic instability creates clones more prone to resistance and progression, the natural history may be aborted. This may be a partial explanation of why some patients in complete molecular remission may be removed from TKI therapy. (c) Once resistance allows unopposed Bcr-Abl signaling, more resistant clones can emerge. Thus, the likelihood of eventual resistance to the second TKI is high, as is the probability of new mutations emerging. Figure not to scale.