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

Myeloblastosis-associated virus 2 (MAV-2) is a highly tumorigenic simple avian retrovirus. Chickens infected in ovo with MAV-2 develop tumors in the kidneys, lungs, and liver with a short latency, less than 8 weeks. Here we report the results of molecular analyses of MAV-2-induced liver tumors that fall into three classes: hepatic hemangiosarcomas (HHSs), intrahepatic cholangiocarcinomas (ICCs), and hepatocellular carcinomas (HCCs). Comprehensive inverse PCR-based screening of 92 chicken liver tumors revealed that in ca. 86% of these tumors, MAV-2 provirus had integrated into one of four gene loci: HRAS, EGFR, MET, and RON Insertionally mutated genes correlated with tumor type: HRAS was hit in HHSs, MET in ICCs, RON mostly in ICCs, and EGFR mostly in HCCs. The provirus insertions led to the overexpression of the affected genes and, in the case of EGFR and RON, also to the truncation of exons encoding the extracellular ligand-binding domains of these transmembrane receptors. The structures of truncated EGFR and RON closely mimic the structures of oncogenic variants of these genes frequently found in human tumors (EGFRvIII and sfRON).IMPORTANCE These data describe the mechanisms of oncogenesis induced in chickens by the MAV-2 retrovirus. They also show that molecular processes converting cellular regulatory genes to cancer genes may be remarkably similar in chickens and humans. We suggest that the MAV-2 retrovirus-based model can complement experiments performed using mouse models and provide data that could translate to human medicine.

• Klíčová slova
• avian retroviruses, insertional mutagenesis, retroviral oncogenesis,
• MeSH
• cholangiokarcinom genetika   virologie   MeSH
• geny erbB-1 * MeSH
• hemangiosarkom genetika   virologie   MeSH
• hepatocelulární karcinom genetika   virologie   MeSH
• integrace viru MeSH
• inzerční mutageneze * MeSH
• karcinogeneze * MeSH
• kur domácí genetika   MeSH
• lidé MeSH
• nádory jater genetika   virologie   MeSH
• onkogeny MeSH
• protoonkogenní proteiny c-met genetika   MeSH
• proviry genetika   fyziologie   MeSH
• ptačí proteiny genetika   MeSH
• tyrosinkinasové receptory genetika   MeSH
• virus ptačí myeloblastózy genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protoonkogenní proteiny c-met MeSH
• ptačí proteiny MeSH
• RON protein MeSH Prohlížeč
• tyrosinkinasové receptory MeSH