Myelodysplastic Syndromes: Classification and Transformation

Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic morphology in one or more myeloid lineages, and a variable risk of transformation to acute myeloid leukemia (AML). The pathogenesis involves acquired somatic mutations in hematopoietic stem cells (most commonly in genes regulating RNA splicing [SF3B1, SRSF2, U2AF1], epigenetic modification [TET2, DNMT3A, IDH1/2, ASXL1], transcription factors [RUNX1, ETV6], and tumor suppressors [TP53]) that confer a proliferative advantage while impairing normal differentiation and maturation. The result is a paradox of hypercellular bone marrow (clonal expansion) with peripheral blood cytopenias (ineffective hematopoiesis — cells die before reaching maturity via increased intramedullary apoptosis). Morphological hallmarks include dysplastic changes in erythroid (megaloblastic changes, nuclear budding, ring sideroblasts — iron-laden mitochondria surrounding the nucleus), myeloid (hypogranular neutrophils, pseudo-Pelger-Huet nuclear hypolobation), and megakaryocytic (micromegakaryocytes, separated nuclear lobes) lineages. The WHO classification and the Revised International Prognostic Scoring System (IPSS-R) stratify MDS by cytogenetic abnormalities, blast percentage, depth of cytopenias, and molecular mutations into risk categories that guide treatment decisions. Low-risk MDS (IPSS-R very low and low) is managed with...