Polycomb protein RING1A limits hematopoietic differentiation in myelodysplastic syndromes

// Anna Palau 1, 2, 6 , Anne-Kathrin Garz 3, 4 , Jeannine Diesch 1 , Anabel Zwick 3 , Roberto Malinverni 1 , Vanesa Valero 1 , Katrina Lappin 5 , Raquel Casquero 1, 2 , Andreas Lennartsson 6 , Johannes Zuber 7 , Tomas Navarro 1, 8 , Ken I. Mills 5 , Katharina S. Gotze 3, 4 and Marcus Buschbeck 1, 2 1 Josep Carreras Leukaemia Research Institute, Campus ICO-Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain 2 Program for Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain 3 Department of Medicine III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 4 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, United Kingdom 6 Current address: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden 7 Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria 8 Clinical Hematology Department, ICO-Hospital GermansTrias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain Correspondence to: Marcus Buschbeck, email: mbuschbeck@carrerasresearch.org Katharina S. Gotze, email: katharina.goetze@tum.de Keywords: myelodysplastic syndromes; polycomb repressive complexes; epigenetic regulation; hematopoietic stem cells; cellular differentiation Received: April 04, 2017     Accepted: November 11, 2017     Published: December 01, 2017 ABSTRACT Genetic lesions affecting epigenetic regulators are frequent in myelodysplastic syndromes (MDS). Polycomb proteins are key epigenetic regulators of differentiation and stemness that act as two multimeric complexes termed polycomb repressive complexes 1 and 2, PRC1 and PRC2, respectively. While components and regulators of PRC2 such as ASXL1 and EZH2 are frequently mutated in MDS and AML, little is known about the role of PRC1. To analyze the role of PRC1, we have taken a functional approach testing PRC1 components in loss- and gain-of-function experiments that we found overexpressed in advanced MDS patients or dynamically expressed during normal hematopoiesis. This approach allowed us to identify the enzymatically active component RING1A as the key PRC1 component in hematopoietic stem cells and MDS. Specifically, we found that RING1A is expressed in CD34 + bone marrow progenitor cells and further overexpressed in high-risk MDS patients. Knockdown of RING1A in an MDS-derived AML cell line facilitated spontaneous and retinoic acid-induced differentiation. Similarly, inactivation of RING1A in primary CD34 + cells augmented erythroid differentiation. Treatment with a small compound RING1 inhibitor reduced the colony forming capacity of CD34 + cells from MDS patients and healthy controls. In MDS patients higher RING1A expression associated with an increased number of dysplastic lineages and blasts. Our data suggests that RING1A is deregulated in MDS and plays a role in the erythroid development defect.