Oncotarget

Research Papers:

Polycomb protein RING1A limits hematopoietic differentiation in myelodysplastic syndromes

Anna Palau, Anne-Kathrin Garz, Jeannine Diesch, Anabel Zwick, Roberto Malinverni, Vanesa Valero, Katrina Lappin, Raquel Casquero, Andreas Lennartsson, Johannes Zuber, Tomàs Navarro, Ken I. Mills, Katharina S. Götze and Marcus Buschbeck _

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Oncotarget. 2017; 8:115002-115017. https://doi.org/10.18632/oncotarget.22839

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Abstract

Anna Palau1,2,6, Anne-Kathrin Garz3,4, Jeannine Diesch1, Anabel Zwick3, Roberto Malinverni1, Vanesa Valero1, Katrina Lappin5, Raquel Casquero1,2, Andreas Lennartsson6, Johannes Zuber7, Tomàs Navarro1,8, Ken I. Mills5, Katharina S. Götze3,4 and Marcus Buschbeck1,2

1Josep Carreras Leukaemia Research Institute, Campus ICO-Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain

2Program for Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain

3Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

4German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

5Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, United Kingdom

6Current address: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

7Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria

8Clinical Hematology Department, ICO-Hospital GermansTrias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain

Correspondence to:

Marcus Buschbeck, email: mbuschbeck@carrerasresearch.org

Katharina S. Götze, 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.


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