From ribosomal stress to clonal adaptation: Del(5q) MDS as a paradigmatic acquired ribosomopathy.

Ribosomopathies reveal how defects in ribosome biogenesis generate lineage-specific hematopoietic phenotypes and create selection pressure that shapes clonal evolution. Using the germline ribosomopathies Diamond-Blackfan anemia and Shwachman-Diamond syndrome to inform a conceptual framework, we examine del(5q) myelodysplastic neoplasm as a paradigmatic acquired ribosomopathy. We propose that disease trajectory is governed not only by the initiating ribosomal defect, but by adaptive responses to persistent ribosomal stress, including compensatory rescue mutations, p53 checkpoint bypass, and internalization of ribosomal stress. This framework links lineage-specific failure, inflammatory niche remodeling, and p53-driven progression to therapeutic vulnerabilities, offering a rationale for risk stratification and targeted treatment in ribosome-stressed myeloid neoplasms.