Abstract
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 × 109/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.
Highlights
Myelodysplastic syndromes (MDS), a heterogeneous clonal myeloid neoplasm characterized by ineffective hematopoiesis leading to cytopenia(s) and a risk of leukemia transformation[1], is one of the most frequently encountered acquired bone marrow failure (BMF)Ineffective erythropoiesis refers to the inability to produce adequate red blood cells (RBCs) with increased dysplastic erythroid precursors in the BM
The hematopoietic stem cells (HSCs) and megakaryocytic-erythroid progenitors (MEPs) in the BM mononuclear cells (BMMNCs) of MDS patients (n = 31) were measured by flow cytometry and in vitro colony-forming unit cell (CFU-C) were assayed in 612 MDS patients, and we found that the percentage of HSCs and MEPs in the BMMNCs, the numbers of burst-forming unit-erythroid (BFU-E) and colony forming unit-erythroid (CFU-E) of MDS patients were sifgnificantly reduced compared with health controls
Patients and inducing differentiation towards erythroid lineage ex vivo, we confirmed the impairments of erythropoietic activity in BM of MDS and, for the first time, found the precocity and premature aging occurring in MDS erythroid cells
Summary
Ineffective erythropoiesis refers to the inability to produce adequate red blood cells (RBCs) with increased dysplastic erythroid precursors in the BM. Anemia is the most common symptom in MDS which correlates with ineffective erythropoiesis. Previous studies suggested that the deficiencies of erythroid lineage of MDS patients were more pronounced than other myeloid lineages[4], highlighting the widespread ineffective erythropoiesis in MDS. Ineffective erythropoiesis in MDS has long been attributed to the differentiation arrest and increased apoptosis. Huang et al Blood Cancer Journal (2020)10:83 of erythroid precursors induced by different mechanisms, such as genetic lesions originating in HSCs, excessive proinflammatory cytokines and immune disorders[3,5,6,7]. A reliable biomarker to accurately reflect the severity of BM ineffective erythropoiesis has been lacking so far and its prognostic significance remains to be carefully defined
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
