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The underlying mechanisms and clinical significance of ineffective erythropoiesis in myelodysplastic syndromes (MDS) remain to be fully defined. We conducted the ex vivo erythroid differentiation of megakaryocytic-erythroid progenitors (MEPs) from MDS patients and discovered that patient-derived erythroblasts exhibit precocity and premature aging phenotypes, partially by inducing the pro-aging genes, like  ERCC1 . Absolute reticulocyte count (ARC) was chosen as a biomarker to evaluate the severity of ineffective erythropoiesis in 776 MDS patients. We found that patients with severe ineffective erythropoiesis displaying lower ARC (<20 × 10 9 /L), were more likely to harbor complex karyotypes and high-risk somatic mutations ( p  < 0.05). Lower ARCs are associated with shorter overall survival (OS) in univariate analysis ( p  < 0.001) and remain significant in multivariable analysis. Regardless of patients of lower-risk who received immunosuppressive therapy or higher-risk who received decitabine treatment, patients with lower ARC had shorter OS ( p  < 0.001). Whereas no difference in OS was found between patients receiving allo-hematopoietic stem cell transplantations (Allo-HSCT) ( p  = 0.525). Our study revealed that ineffective erythropoiesis in MDS may be partially caused by premature aging and apoptosis during erythroid differentiation. MDS patients with severe ineffective erythropoiesis have significant shorter OS treated with immunosuppressive or hypo-methylating agents, but may benefit from Allo-HSCT.

Severe ineffective erythropoiesis discriminates prognosis in myelodysplastic syndromes: analysis based on 776 patients from a single centre