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

Julia Weber, Jorge de la 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. HoffmanJulia 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, Roland Rad

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13 Citations (Scopus)

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.

Original languageEnglish
Article number1415
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

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