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

Julia Weber, Jorge Rosa, Carolyn S. Grove, Markus Schick, Lena Rad, Olga Baranov, Alexander Strong, Anja Pfaus, Mathias J. Friedrich, Thomas Engleitner, Robert Lersch, Rupert Öllinger, Michael Grau, Irene Gonzalez Menendez, Manuela Martella, Ursula Kohlhofer, Ruby Banerjee, Maria A. Turchaninova, Anna Scherger, Gary J. Hoffman, Julia Hess, Laura B. Kuhn, Tim Ammon, Johnny Kim, Günter Schneider, Kristian Unger, Ursula Zimber-Strobl, Mathias Heikenwälder, Marc Schmidt-Supprian, Fengtang Yang, Dieter Saur, Pentao Liu, Katja Steiger, Dmitriy M. Chudakov, Georg Lenz, Leticia Quintanilla-Martinez, Ulrich Keller, George S. Vassiliou, Juan Cadiñanos, Allan Bradley and Roland Rad ()
Additional contact information
Julia Weber: Technische Universität München
Jorge Rosa: Genome Campus, Hinxton
Carolyn S. Grove: Genome Campus, Hinxton
Markus Schick: Technische Universität München
Lena Rad: Genome Campus, Hinxton
Olga Baranov: Technische Universität München
Alexander Strong: Genome Campus, Hinxton
Anja Pfaus: Technische Universität München
Mathias J. Friedrich: Technische Universität München
Thomas Engleitner: Technische Universität München
Robert Lersch: Technische Universität München
Rupert Öllinger: Technische Universität München
Michael Grau: University Hospital Münster
Irene Gonzalez Menendez: Eberhard Karls Universität Tübingen
Manuela Martella: Eberhard Karls Universität Tübingen
Ursula Kohlhofer: Eberhard Karls Universität Tübingen
Ruby Banerjee: Genome Campus, Hinxton
Maria A. Turchaninova: Privolzhsky Research Medical University
Anna Scherger: Technische Universität München
Gary J. Hoffman: Genome Campus, Hinxton
Julia Hess: Research Unit Radiation Cytogenetics
Laura B. Kuhn: Research Unit Gene Vectors
Tim Ammon: Technische Universität München
Johnny Kim: Max-Planck-Institute for Heart and Lung Research
Günter Schneider: Technische Universität München
Kristian Unger: Research Unit Radiation Cytogenetics
Ursula Zimber-Strobl: Research Unit Gene Vectors
Mathias Heikenwälder: German Cancer Research Center (DKFZ)
Marc Schmidt-Supprian: Technische Universität München
Fengtang Yang: Genome Campus, Hinxton
Dieter Saur: Technische Universität München
Pentao Liu: Genome Campus, Hinxton
Katja Steiger: Technische Universität München
Dmitriy M. Chudakov: Privolzhsky Research Medical University
Georg Lenz: University Hospital Münster
Leticia Quintanilla-Martinez: Eberhard Karls Universität Tübingen
Ulrich Keller: Technische Universität München
George S. Vassiliou: Genome Campus, Hinxton
Juan Cadiñanos: Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA)
Allan Bradley: Genome Campus, Hinxton
Roland Rad: Technische Universität München

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09180-3

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