Figure 2.

Clonal evolution of relapses from HD ALL. (a) The two major patterns of leukemia evolution characterized by the predominant progression of the initial clone (left) and the selection of an ancestral clone (right), exemplarily shown in case UPN 545 and UPN 430. AF denotes the AF of all somatic mutations ⩾10 at diagnosis (Dx) and relapse (Rel) to better illustrate the kinetics of clones. Colored lines connecting individual mutations between diagnosis and relapse visualize the kinetics of major and minor populations; gray, shared mutations; blue, diagnosis-specific mutations in the major clone; black, diagnosis-specific mutations in minor clones; red, initially subclonal mutations developing into the major relapse clone; light and dark green, relapse-specific mutations characterizing major and minor clones, respectively. (b) Kinetics of clones in case UPN 715 inferred from copy number-adjusted AFs of mutations present at diagnosis, first and third relapse. Red and pink, shared relapse-specific mutations; purple and yellow, third relapse-specific mutations in major and minor clones, respectively; remaining color code as in (a). (c) Model for the evolution of initial and two relapse leukemias from case UPN 715 derived from AFs shown in (b). Non-disjunction of chromosomes as the presumed first event occurs in a stem or progenitor cell and generates the HD clone. The founding clone harbors additional mutations and is preserved at both relapses (mutation cluster gray). Within this founder clone, specific major (blue) and minor (black) leukemic populations are present at diagnosis, whereas relapses share two additional mutations, and also comprise distinctive mutations. Affected genes are provided in Supplementary Table S6.