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

• Authors: WEBER J.; DELA ROSA J.; GROVE C.S.; SCHICK M.; RAD L.; BARANOVT 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.; KUH L.B.; AMMON T.; KIM J.; SCHNEIDER G.; UNGER K.; ZIMBER-STROBL U.; HEIKENWALDER M.; SCHMIDT-SUPPRIAN M.; YANG F.T.; SAUR D.; LIU P.T.; STEIGER K.; CHUDAKOV Dmitriy; LENZ G.; QUINTANILLA-MARTINEZ L.; KELLER U.; VASSILIOU G.S.; CADINANOS J.; BRADLEY A.; RAD R.
• Year of publication: 2019
• Type: Article in Periodical
• Magazine / Source: Nature Communications
• MU Faculty or unit: Central European Institute of Technology
• Web: https://www.nature.com/articles/s41467-019-09180-3
• Doi: http://dx.doi.org/10.1038/s41467-019-09180-3
• Keywords: CANCER GENE DISCOVERY; SLEEPING-BEAUTY; CHROMOSOMAL TRANSPOSITION; INSERTIONAL MUTAGENESIS; THERAPEUTIC TARGETS; CODING GENOME; MOUSE MODEL; PATHOGENESIS; ACTIVATION; MUTATION
• Description: 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.