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

## TL;DR

Erythropoietin treatment disrupts B cell development in mice, leading to the emergence of cells with mixed myeloid and B cell traits.

## Contribution

The study reveals a novel effect of EPO on early B cell development, promoting myeloid-like B cell progenitors during stress hematopoiesis.

## Key findings

- EPO promotes a transition from common lymphoid progenitors to pre-pro-B cells but impairs the next developmental stage.
- EPO exposure leads to the emergence of atypical B cell precursors expressing myeloid markers.
- EPO reprograms B cell precursors by upregulating myeloid genes and downregulating B cell identity genes.

## Abstract

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.

•EPO induces a novel CLP population expressing M-CSFR, a myeloid commitment marker•Exposure to EPO adversely impacts early B lymphopoiesis•EPO reprograms lymphoid progenitors by imprinting a myeloid molecular signature•B lymphoid precursors from EPO-exposed mice downregulate the IL7-receptor

EPO induces a novel CLP population expressing M-CSFR, a myeloid commitment marker

Exposure to EPO adversely impacts early B lymphopoiesis

EPO reprograms lymphoid progenitors by imprinting a myeloid molecular signature

B lymphoid precursors from EPO-exposed mice downregulate the IL7-receptor

EPO is a master regulator of hematopoiesis with immuno-hematopoietic roles and macrophage-mediated tissue-repair effects. Hacein-Bey-Abina et al. show that sustained EPO during stress hematopoiesis redirects lymphoid progenitors toward a myeloid-imprinted fate, both at the transcriptomic and phenotypic levels, producing atypical “myeloid-like” B cells. EPO may act upstream in the bone marrow to regulate lineage plasticity, influencing inflammation resolution and repair processes.