UBE2O AS A KEY REGULATOR OF DRUG-INDUCED ERYTHROPOIESIS IN THE CONTEXT OF MYELODYSPLASTIC SYNDROMES

Erythropoiesis is a tightly regulated process essential for maintaining adequate red blood cell levels, and its disruption contributes to hematological disorders such as myelodysplastic syndromes. This study focuses on the ubiquitin-conjugating enzyme UBE2O and its role during terminal erythroid differentiation. We demonstrate that UBE2O expression is dynamically regulated by erythropoiesis-stimulating agents, including erythropoietin and the TGF-β pathway inhibitor luspatercept, and positively correlates with the master erythroid transcription factor GATA1. Using in vitro models, we reveal that UBE2O upregulation accompanies erythroid maturation, while its silencing impairs terminal differentiation, highlighting its functional relevance. Chromatin immunoprecipitation assays confirm direct transcriptional regulation of UBE2O by GATA1, establishing a mechanistic link within the erythroid transcriptional network. Analysis of primary samples from MDS patients further supports the association between UBE2O expression and erythroid stimulation in vivo, suggesting its potential contribution to the response to treatments. To advance physiological relevance, we developed bone marrow organoids derived from human induced pluripotent stem cells, providing a novel platform to investigate ubiquitination pathways during erythropoiesis. Overall, this work identifies UBE2O as a critical regulator of erythroid differentiation and proposes its modulation as a potential therapeutic strategy to improve ineffective erythropoiesis in MDS