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.
- MeSH
- B-buněčný lymfom genetika patologie MeSH
- buněčné klony MeSH
- CRISPR-Cas systémy genetika MeSH
- genetické asociační studie MeSH
- genetické testování metody MeSH
- genová dávka MeSH
- geny nádorové MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- receptory antigenů B-buněk metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- reprodukovatelnost výsledků MeSH
- transpozibilní elementy DNA genetika MeSH
- tumor supresorové geny MeSH
- ztráta heterozygozity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- receptory antigenů B-buněk MeSH
- transpozibilní elementy DNA MeSH
