Weber, J., de la Rosa, J., Grove, C. S., Schick, M., Rad, L., Baranov, O., Strong, A., Pfaus, A., Friedrich, M. J., Engleitner, T., Lersch, R., Ollinger, R., Grau, M., Menendez, I. G., Martella, M., Kohlhofer, U., Banerjee, R., Turchaninova, M. A., Scherger, A., Hoffman, G. J., Hess, J., Kuhn, L. B., Ammon, T., Kim, J., Schneider, G., Unger, K., Zimber-Strobl, U., Heikenwalder, M., Schmidt-Supprian, M., Yang, F., Saur, D., Liu, P., Steiger, K., Chudakov, D. M., Lenz, G., Quintanilla-Martinez, L., Keller, U., Vassiliou, G. S., Cadinanos, J., Bradley, A., and Rad, R. (2019). Nat Commun 10, 1415

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.