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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Weber, Julia 
Grove, Carolyn S 
Schick, Markus 
Rad, Lena 

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.

Description

Keywords

Animals, CRISPR-Cas Systems, Clone Cells, DNA Transposable Elements, Gene Dosage, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Genes, Tumor Suppressor, Genetic Association Studies, Genetic Testing, Humans, Loss of Heterozygosity, Lymphoma, B-Cell, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Antigen, B-Cell, Reproducibility of Results

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

10

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_PC_12009)