Novel evidence that the ABO blood group shapes erythropoiesis and results in higher hematocrit for blood group B carriers.

The ABO blood group (BG) system is of great importance for blood transfusion and organ transplantation. Since the same transcription factors (TFs) and microRNAs (miRNAs) govern the expression of ABO BG antigens and regulate erythropoiesis, we hypothesized functional connections between both processes. We found significantly higher hemoglobin and hematocrit values in BG B blood donors compared to BG A. Furthermore, we observed that erythropoiesis in BG B hematopoietic stem/progenitor cells (HSPCs) was accelerated compared to BG A HSPCs. Specifically, BG B HSPCs yielded more lineage-specific progenitors in a shorter time (B: 31.3 ± 2.2% vs. A: 22.5 ± 3.0%). Moreover, non-BG A individuals exhibited more terminally differentiated RBCs with higher enucleation rates containing more hemoglobin compared to BG A. Additionally, we detected increased levels of miRNA-215-5p and -182-5p and decreased expression of their target TFs RUNX1 and HES-1 mRNAs in erythroid BG B precursor cells compared to BG A. This highlights the important roles of these factors for the disappearance of differentiation-specific glycan antigens and the appearance of cancer-specific glycan antigens. Our work contributes to a deeper understanding of erythropoiesis gene regulatory networks and identifies its interference with BG-specific gene expression regulations particularly in diseases, where ABO BGs determine treatment susceptibility and disease progression.