Polycomb protein RING1A limits hematopoietic differentiation in myelodysplastic syndromes

Abstract

Genetic mutations affecting epigenetic regulators are commonly observed in myelodysplastic syndromes (MDS). Polycomb proteins, which are crucial for regulating differentiation and stem cell properties, operate through two major complexes: Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2). While mutations in components and regulators of PRC2, such as ASXL1 and EZH2, are frequently seen in MDS and acute myeloid leukemia (AML), the role of PRC1 is less understood. To investigate PRC1′s function, we conducted experiments examining its components in both loss- and gain-of-function settings. We discovered that these components are either overexpressed in advanced MDS cases or dynamically expressed during normal blood cell formation. Our research pinpointed RING1A, an enzymatically active component of PRC1, as a key player in hematopoietic stem cells and MDS. RING1A is present in CD34+ bone marrow progenitor cells and is found at elevated levels in high-risk MDS patients. Reducing RING1A levels in an MDS-derived AML cell line promoted both spontaneous and retinoic acid-induced differentiation. Similarly, inactivation of RING1A in primary CD34+ cells enhanced erythroid differentiation. Moreover, treating CD34+ cells from both MDS patients and healthy individuals with a RING1 inhibitor decreased their colony-forming ability. Higher RING1A expression in MDS patients was associated with an increased number of dysplastic cell lineages and blasts. Our findings suggest that RING1A is dysregulated in MDS and contributes to defects in erythroid CPI-1205 development.