PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice.

Autor: Weber J; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany., de la Rosa J; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Grove CS; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.; School of Medicine, University of Western Australia, Crawley, 6009, Australia.; Department of Haematology, PathWest and Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Nedlands, 6009, Australia., Schick M; Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany., Rad L; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Baranov O; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany., Strong A; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Pfaus A; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany., Friedrich MJ; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany., Engleitner T; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany., Lersch R; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany., Öllinger R; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany., Grau M; Department of Medicine A, University Hospital Münster, Münster, 48149, Germany.; Cluster of Excellence EXC 1003, Cells in Motion, Münster, 48149, Germany., Menendez IG; Institute of Pathology and Comprehensive Cancer Center, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany., Martella M; Institute of Pathology and Comprehensive Cancer Center, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany., Kohlhofer U; Institute of Pathology and Comprehensive Cancer Center, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany., Banerjee R; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Turchaninova MA; Laboratory of Genomics of Antitumor Adaptive Immunity, Privolzhsky Research Medical University, Nizhny Novgorod, 603005, Russia.; Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, 117997, Russia.; Pirogov Russian National Research Medical University, Moscow, 117997, Russia., Scherger A; Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany., Hoffman GJ; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.; School of Medicine, University of Western Australia, Crawley, 6009, Australia., Hess J; Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, Neuherberg, 85764, Germany., Kuhn LB; Helmholtz Zentrum München, Research Unit Gene Vectors, Munich, 81377, Germany., Ammon T; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany., Kim J; Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.; German Center for Cardiovascular Research (DZHK), Rhine Main, Germany., Schneider G; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany., Unger K; Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, Neuherberg, 85764, Germany., Zimber-Strobl U; Helmholtz Zentrum München, Research Unit Gene Vectors, Munich, 81377, Germany., Heikenwälder M; Divison of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany., Schmidt-Supprian M; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany., Yang F; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Saur D; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany.; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany., Liu P; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.; Li Ka Shing Faculty of Medicine, Stem Cell and Regenerative Medicine Consortium, School of Biomedical Sciences, University of Hong Kong, Hong Kong, China., Steiger K; Comparative Experimental Pathology, Technische Universität München, Munich, 81675, Germany., Chudakov DM; Laboratory of Genomics of Antitumor Adaptive Immunity, Privolzhsky Research Medical University, Nizhny Novgorod, 603005, Russia.; Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, 117997, Russia.; Pirogov Russian National Research Medical University, Moscow, 117997, Russia.; Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia.; Center of Molecular Medicine, CEITEC, Masaryk University, Brno, 601 77, Czech Republic., Lenz G; Department of Medicine A, University Hospital Münster, Münster, 48149, Germany.; Cluster of Excellence EXC 1003, Cells in Motion, Münster, 48149, Germany., Quintanilla-Martinez L; Institute of Pathology and Comprehensive Cancer Center, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany., Keller U; Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany.; Hematology and Oncology-Campus Benjamin Franklin (CBF), Charité-Universitätsmedizin Berlin, Berlin, 12203, Germany., Vassiliou GS; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.; Wellcome Trust-MRC Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, CB2 0XY, Cambridge, UK.; Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, CB2 0PT, UK., Cadiñanos J; Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, 33193, Spain.; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, 33006, Spain., Bradley A; The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Rad R; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, 81675, Germany. Roland.Rad@tum.de.; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, 81675, Germany. Roland.Rad@tum.de.; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany. Roland.Rad@tum.de.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany. Roland.Rad@tum.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Mar 29; Vol. 10 (1), pp. 1415. Date of Electronic Publication: 2019 Mar 29.
DOI: 10.1038/s41467-019-09180-3
Abstrakt: B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.
Databáze: MEDLINE