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

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 × 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.

Low Plasma Citrate Levels and Specific Transcriptional Signatures Associated with Quiescence of CD34+ Progenitors Predict Azacitidine Therapy Failure in MDS/AML Patients

“…In accordance with this concept, multiple properties of the PD patients’ cells resembled aged HSCs, including the most markedly differentially overexpressed ribosomal gene set [ 42 ]. These data are also consistent with the concept of premature aging of MDS HSCs [ 74 ] and progenitors [ 75 ]. The non-cycling status and low replication rate signature were also associated with decreased expression of the replication-dependent histone genes of the HIST1 cluster, which are the most represented genes among the PD patients’ top 50 downregulated genes.…”

A Review of Key Regulators of Steady-State and Ineffective Erythropoiesis

“…ARC (Absolute reticulocyte count) in peripheral blood was found to be a biomarker (when ARC < 20 × 10 9 /L) together with a shorter overall survival in the evaluation of the severity of ineffective erythropoiesis in 776 MDS patients. Huang et al concluded that the inadequate production of red blood cells in MDS may be partly due to premature ageing and apoptosis during erythroid differentiation as well as high-risk molecular genetic aberrations due to the altered expression of the ERCC1 gene [95].…”