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

Weber, Julia; de la Rosa, Jorge; Grove, Carolyn S; Schick, Markus; Rad, Lena; Baranov, Olga; Strong, Alexander; Pfaus, Anja; Friedrich, Mathias J; Engleitner, Thomas; Lersch, Robert; Öllinger, Rupert; Grau, Michael; Menendez, Irene Gonzalez; Martella, Manuela; Kohlhofer, Ursula; Banerjee, Ruby; Turchaninova, Maria A; Scherger, Anna; Hoffman, Gary J; Hess, Julia; Kuhn, Laura B; Ammon, Tim; Kim, Johnny; Schneider, Günter; Unger, Kristian; Zimber-Strobl, Ursula; Heikenwälder, Mathias; Schmidt-Supprian, Marc; Yang, Fengtang; Saur, Dieter; Liu, Pentao; Steiger, Katja; Chudakov, Dmitriy M; Lenz, Georg; Quintanilla-Martinez, Leticia; Keller, Ulrich; Vassiliou, George S; Cadiñanos, Juan; Bradley, Allan; Rad, Roland     «

Weber, Julia; de la Rosa, Jorge; Grove, Carolyn S; Schick, Markus; Rad, Lena; Baranov, Olga; Strong, Alexander; Pfaus, Anja; Friedrich, Mathias J; Engleitner, Thomas; Lersch, Robert; Öllinger, Rupert; Grau, Michael; Menendez, Irene Gonzalez; Martella, Manuela; Kohlhofer, Ursula; Banerjee, Ruby; Turchaninova, Maria A; Scherger, Anna; Hoffman, Gary J; Hess, Julia; Kuhn, Laura B; Ammon, Tim; Kim, Johnny; Schneider, Günter; Unger, Kristian; Zimber-Strobl, Ursula; Heikenwälder, Mathias; Schmidt-Suppr...     »

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.      «

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...     »