Evolutionary trajectories of myelodysplastic syndromes/neoplasms

Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of myeloid malignancies characterized by clonality, cytopenia, bone marrow dysplasia, and a variable risk of progression to acute myeloid leukemia (AML). With few therapeutic advances beyond the introduction of hypomethylating agents twenty years ago, MDS remains associated with poor overall survival, limited curative options, and frequent relapse or resistance to available treatments. Breakthroughs in genomic and single-cell technologies have transformed our understanding of MDS pathogenesis, revealing that disease initiation and progression follow stereotyped evolutionary trajectories driven by distinct constellations of somatic mutations and modulated by both endogenous and exogenous factors. In this review, we synthesize current knowledge of the genetic landscape of MDS and dissect the clonal path of the disease from precursor states to AML transformation. We further discuss how germline predisposition, bone marrow microenvironmental remodeling, and exposure to environmental or genotoxic stressors impact the selection, expansion, and transformation potential of the hematopoietic clone. Finally, we outline how these insights have underpinned a conceptual shift toward a molecular taxonomy of myeloid neoplasms, redefining diagnostic boundaries between MDS and AML, improving prognostic stratification, and enabling a biology-driven framework for personalized treatment of MDS.