A. Mutations of SBDS, which are found in the great majority of cases of SDS, result in impaired ribosome biogenesis. The resulting ribosome biogenesis stress induces p53 expression, which in turn, induces HSC growth arrest. B. Persistent ribosome biogenesis stress results in the selection of HSCs that carrying TP53 mutations. Continued ribosome biogenesis stress in HSCs carrying one mutated TP53 allele likely selects for clones that have mutated the second allele, leading to genomic instability and eventual MDS/AML.