Comparison of different clonal evolution models leading to relapse. Clones are represented as in the fish plots in Figure 6, and time goes from left to right from time of disease initiation to relapse. Clone sizes are represented in the vertical direction. Chemotherapy-sensitive clones are indicated in gray, chemotherapy-resistant in red, and persistent clones (able to survive but not proliferate during chemotherapy) in blue. The time of diagnosis and treatment commencement are indicated by a dotted line. (A) The de novo resistance scenario, in which most cells are chemoresistant up-front and remission is never achieved; this was not observed in our cohort. (B) The chemo-selection scenario, in which a minor drug-resistant subclone survives chemotherapy and leads to relapse after an initial remission. Our mathematical modeling suggests that very early relapses (<9 months) are likely due to this mechanism. (C) The chemo-induced mutation scenario, in which no fully resistant subclone is present at the time of diagnosis. The drug-resistant subclone is derived from a population of cells that persisted (survived) during chemotherapy treatment but was not fully drug resistant because it could not actively proliferate sufficiently to cause relapse. This is supported by mutational signature and mathematical modeling in later relapse groups (specifically, the early and late relapse groups).