Model of MDS/AML pathogenesis in SDS, Li Fraumeni syndrome, and tMN. In Li Fraumeni syndrome, all of the HSPCs carry heterozygous TP53 mutations (indicated by blue/red shaded cells). In the absence of genotoxic stress (eg, chemotherapy), there is no selective pressure to mutate the second allele. Thus, MDS/AML in Li Fraumeni syndrome is uncommon. In SDS, mutations of SBDS lead to chronic ribosome stress, which can select for HSPCs that have mutated 1 allele of TP53 and result in TP53-mutated CH. Continued ribosome stress then selects for HSPCs in which both TP53 alleles are mutated (red shaded cells), which ultimately leads to MDS/AML. Patients undergoing treatment with cytotoxic chemotherapy or radiation experience significant genotoxic stress, resulting in selection of HSPCs carrying age-related TP53 mutations. In this model, repeated exposure to cytotoxic therapy selects for HSPCs carrying biallelic TP53 mutations, which ultimately leads to MDS/AML. Other hematopoietic stressors, such as chronic inflammation, may promote progression from CH to myeloid malignancy in a similar fashion by providing a fitness advantage to HSPCs carrying mutations in other genes besides TP53. tAML, therapy-related AML; tMDS, therapy-related MDS.