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

• GATA1-mediated UBE2O upregulation helps promote red blood cell formation upon erythropoiesis stimulation.

• UBE2O downregulation reduces erythroid differentiation capability in HUDEP-2 cell line.

Ineffective erythropoiesis and the resulting anemia are the main characteristics of myelodysplastic syndromes (MDS). Drugs designed to promote erythropoiesis in MDS patients include erythropoiesis-stimulating agents such as recombinant human erythropoietin and TGF-β inhibitors such as luspatercept, which is approved for the treatment of anemia associated with MDS or β-thalassemia. However, these types of drugs are ineffective in some patients and fail to elicit durable responses in others, underscoring the need for additional therapeutic targets. Here, we sought to define the role of UBE2O, a ubiquitin-conjugating enzyme that remodels the proteome during late erythroid differentiation, in the pathogenesis of ineffective erythropoiesis in the setting of MDS and investigate its potential as a therapeutic target for improving erythropoiesis. UBE2O expression was analyzed in K562 leukemic cells and MDS patients' bone marrow samples before and after treatment with erythropoietin and luspatercept. Bioinformatic analysis identified a GATA1 binding motif on the UBE2O promoter region, and chromatin immunoprecipitation validated the interaction. Our findings demonstrate that GATA1 binds to the UBE2O promoter, thereby regulating UBE2O transcription and expression. Although further studies are needed to explore the implications of UBE2O in MDS treatment, our work provides potential strategies for novel therapeutic approaches in MDS.