Extended Data Figure 3. Model of how cytotoxic therapy shapes clonal evolution in t-AML/t-MDS.

Age-related mutations in hematopoietic stem/progenitor cells (HSPCs) result in the production of a genetically heterogeneous population of HSPCs, including rare HSPCs with heterozygous TP53 mutations in some individuals. During chemotherapy and/or radiotherapy for the primary cancer, HSPC clones harboring a TP53 mutation have a selective growth advantage, resulting in expansion of that clone. Subsequent acquisition of additional driver mutations results in transformation to t-AML/t-MDS. Of note, the presence of TP53 mutations likely accounts for this high incidence of cytogenetic abnormalities in t-AML/t-MDS and poor response to chemotherapy.