Erythropoietin exposure disrupts B cell development and drives the emergence of myeloid-biased biphenotypic progenitors

Recombinant human erythropoietin (EPO) is widely used to treat anemia. EPO has immunomodulatory effects extending beyond erythropoiesis, but its impact on lympho-hematopoiesis remains insufficiently explored. The objective of this study was to investigate B lymphopoiesis in the context of hyper-EPOemia-induced stress hematopoiesis. Using an EPO supplementation model in C57BL/6 mice, we found that EPO exerts contrasting effects on early B cell development. EPO supplementation promotes the transition from common lymphoid progenitors (CLPs) to pre-pro-B cells but impairs the pre-pro-B to pro-B transition, in part by downregulating interleukin-7 (IL-7) receptor expression. Remarkably, EPO promotes the emergence of atypical B cell precursors, including M-CSFR/CD115-expressing CLPs and CD11b and CD16/32-expressing pre-pro-B cells. Gene expression profiling revealed that EPO reprograms early B cell precursors, upregulating myeloid-type genes, while downregulating B lymphoid identity genes. In conclusion, our results show that hyper-EPOemia interferes with the earliest stages of B cell development, while promoting the emergence of mixed-lineage "myeloid-like" B cells.