Single-cell sequencing of a secondary acute myeloid leukemia (sAML) case from the study of Dr. Menssen and colleagues illustrates how the dynamic clonal architecture can be inferred by the subclonal mutation patterns. A) An initial clone carrying SRSF2 (spliceosome) and ASXL1 (epigenetic) mutations subsequently acquired a RUNX1 mutation (transcription) and then a PTPN11 mutation (signaling) as the final dominant clone in the sAML; a smaller subclone instead acquired NRAS, another signaling mutation. B) Complex clonal evolution pathways of signaling gene mutations in the progression from MDS to sAML. While a large subset of patients (26%) acquired a new signaling gene mutation upon development of sAML, significant subsets had pre-existing mutations that expanded (7%) or contracted (9%). Complex patterns were also observed (lower four panels) in which some subclones persisted simultaneously with the acquisition or loss of signaling mutations in other clones. (Adapted from Figure 3A and Figure 5D from Menssen AJ. Convergent clonal evolution of signaling gene mutations is a hallmark of myelodysplastic syndrome progression. Blood Cancer Discov. 2022;3[4]:330-345.)