Fig. 7. TP53 and EIF6 mutations define distinct pathways of somatic clonal progression and distinguish leukemia predisposition in SDS.

Germline context drives separate compensatory and maladaptive somatic pathways of clonal evolution in patients with SDS. Germline SBDS mutations result in ribosomal stress which activate TP53 checkpoint pathways and promote bone marrow failure. EIF6 mutations alleviate the underlying ribosome maturation defects which reduces p53 checkpoint activation and improves cell fitness. TP53 mutations eliminate checkpoint pathways to improve relative fitness without improving the underlying ribosomal abnormalities, and promote the development of myeloid malignancies.