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- Title
PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice.
- Authors
Weber, Julia; de la Rosa, Jorge; Grove, Carolyn S.; Schick, Markus; Rad, Lena; Baranov, Olga; Strong, Alexander; Pfaus, Anja; Friedrich, Mathias J.; Engleitner, Thomas; Lersch, Robert; Öllinger, Rupert; Grau, Michael; Menendez, Irene Gonzalez; Martella, Manuela; Kohlhofer, Ursula; Banerjee, Ruby; Turchaninova, Maria A.; Scherger, Anna; Hoffman, Gary J.
- 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. Identification of cancer genes altered by non-genetic mechanisms in B-cell lymphoma is challenging. Here, the authors report the development of transposon tools to perform genome-wide recessive screens in vivo and validate identified putative tumor suppressor genes using a CRISPR/Cas9 validation platform.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-09180-3