Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic neoplasms defined by morphologic dysmorphia, one or more blood cytopenias, and an increased risk of clonal evolution to acute myelogenous leukemia (AML).* These disorders can occur at any age but have an incidence that rises exponentially after age 40 years with a median age at diagnosis of 72 years. Most cases are acquired de novo through the accumulation of somatic mutations, although a small fraction arises after exposure to DNA damaging agents, such as chemotherapy and radiation. A minority of cases are the result of inherited mutations that predispose to the development of MDS and related myeloid disorders. Subtypes of MDS are largely defined by clinical features and range from refractory cytopenias (typically including anemia) to oligoblastic myelogenous leukemia with an increase in marrow myeloblasts (5 to 19 percent). Cases with 20 percent or more myeloblasts in the marrow (an arbitrary boundary) or specific chromosomal translocations are defined as AML. The diagnostic criteria for MDS include dysmorphogenesis in one or more blood cell lineages, often resulting in exaggerated apoptosis during later stages of maturation. Poikilocytosis, anisocytosis, anisochromia, and basophilic stippling are features of the abnormal red cells. The marrow usually contains increased erythroid precursors with dysmorphic features, including nuclear distortions and scanty, poorly hemoglobinized cytoplasm or macroerythroblasts. Pathologic ring sideroblasts are a common feature used to define particular subtypes of MDS. Neutrophils may have bilobed or hypersegmented nuclei and hypogranulated cytoplasm in association with increased marrow granulocyte precursors. Giant and microcytic platelets, sometimes with abnormal or absent granulation, in the blood are associated with megakaryocytic hyperplasia and atypical lobulation of the nucleus, megakaryocyte clustering, and decreased marrow megakaryocyte size. Clonal cytogenetic abnormalities occur in approximately 50 percent of patients, typically as recurrent deletions of entire chromosomes or chromosomal segments. Trisomy 8 is the only frequent copy number gain and recurrent translocations are rare. Various prognostic models for MDS incorporate cytogenetic abnormalities along with marrow blast proportion and blood cytopenias to predict the mortality and risk of clonal evolution to AML. The selection and timing of therapy for MDS is largely driven by risk stratification. Newer prognostic scoring systems have begun to consider somatic mutations as markers of disease-associated risk as pathogenic driver mutations can be identified in almost all cases of MDS and several lesions have a prognostic significance that is independent of other known risk factors. As detectable somatic events, driver mutations are markers of clonal hematopoiesis and could help establish the diagnosis in some cases. Recurrent somatic mutations identify the heterogenous molecular pathways frequently disordered in MDS. These include mutations in multiple components of the RNA splicing machinery, several epigenetic regulators of DNA methylation and histone modifications, various hematopoietic transcription factors, and growth factor signaling pathway members among others. Certain mutations are tightly associated with clinical features including ring sideroblasts, chromosomal instability, and severe cytopenias. Current treatment guidelines for MDS are based on clinical risk assessments and generally ...
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