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

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


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.