Figure 2.

Pathways of somatic clonal evolution in SDS. Somatic blood mutations in TP53 (red) and EIF6 (green) are recurrent in patients with SDS and confer a selective advantage to HSC via distinct mechanisms. Inactivating EIF6 mutations relieve the fitness defect caused by SBDS deficiency by improving ribosome joining and translation efficiency. In contrast, heterozygous TP53 mutations improve HSC fitness by decreasing the cell checkpoint activation (eg, p21) but do not improve the underlying ribosome joining defect. Acquisition of a second TP53 mutation (ie, biallelic TP53-mutated clone) results in the complete loss of cellular checkpoints, genomic instability, and eventual progression to a myeloid malignancy.