Polycomb protein RING1A limits hematopoietic differentiation in myelodysplastic syndromes
Palau de Miguel, Anna (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Garz, Anne-Kathrin (German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany)
Diesch, Jeannine (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Zwick, Anabel (Technische Universität München)
Malinverni, Roberto (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Valero, Vanesa (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Lappin, Katrina (Centre for Cancer Research and Cell Biology. Queen's University)
Casquero, Raquel (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Lennartsson, Andreas (Karolinska Institutet (Estocolm, Suècia). Department of Biosciences and Nutrition)
Zuber, Johannes (Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria)
Navarro, Tomàs (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Mills, Ken I. (Centre for Cancer Research and Cell Biology. Queen's University)
Götze, Katharina S. (German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany)
Buschbeck, Marcus (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Universitat Autònoma de Barcelona

Date:	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.
Grants:	Ministerio de Economía y Competitividad BFU2015-66559-P Ministerio de Economía y Competitividad FJCI-2014-22983 Instituto de Salud Carlos III PIE16-00011
Note:	Altres ajuts: This project was supported by grants from Deutsche José Carreras Leukaemie Stiftung DJCLS R 14/16 (KSG and MB), Radiumhemmets forskningsfonder, the Swedish Cancer foundation and the Swedish Research council (AL), German Cancer Consortium DKTK (AKG), the German Research Council DFG FOR2033 Go 713/2-1 and SFB 1243 A09 (KSG). Research in the Buschbeck lab is further supported by AFM-Téléthon (AFM-18738), the Marie Skłodowska Curie Training network 'ChroMe' (H2020-MSCAITN-2015-675610), and AGAUR (2014-SGR-35). Research at the IJC is supported by the 'La Caixa' Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Programme / Generalitat de Catalunya.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Myelodysplastic syndromes ; Polycomb repressive complexes ; Epigenetic regulation ; Hematopoietic stem cells ; Cellular differentiation
Published in:	Oncotarget, Vol. 8 (december 2017) , p. 115002-115017, ISSN 1949-2553

DOI: 10.18632/oncotarget.22839
PMID: 29383137

16 p, 4.4 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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