Temporal order of mutation acquisition in MDS based on data from Papaemmanuil et al. (A) Analysis of the variant allele fractions in 111 genes sequenced in 738 patients with MDS and related disorders yielded a common pattern of mutation acquisition in the natural history of MDS. Based on this work, it appears that mutations in genes encoding spliceosomal components occur early in the pathogenesis of MDS with mutations in epigenetic modifiers and transcripitional regulators occurring later. Mutations activating cytokine signaling appear to be among the latest clonal events in MDS. In the figure, the width of the box indicates the time frame in which mutations of genes described in the box occurs. The overlap of the boxes indicates the fact the patterns of mutation acquisition in MDS are not absolute. (B) The authors noted that nearly half of MDS patients had ≥2 frequently mutated genes simultaneously. In these individuals, one-third had multiple subclones and an attempt to construct the clonal hierarchy of 1 such individual bearing TET2, SF3B1, and EZH2 mutations from the study is shown.