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Genetic modification of primary human B cells to model high-grade lymphoma

Published version
Peer-reviewed

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Authors

Caeser, Rebecca 
Di Re, Miriam 
Gao, Jie 
Lara-Chica, Maribel  ORCID logo  https://orcid.org/0000-0003-2908-9929

Abstract

Abstract: Sequencing studies of diffuse large B cell lymphoma (DLBCL) have identified hundreds of recurrently altered genes. However, it remains largely unknown whether and how these mutations may contribute to lymphomagenesis, either individually or in combination. Existing strategies to address this problem predominantly utilize cell lines, which are limited by their initial characteristics and subsequent adaptions to prolonged in vitro culture. Here, we describe a co-culture system that enables the ex vivo expansion and viral transduction of primary human germinal center B cells. Incorporation of CRISPR/Cas9 technology enables high-throughput functional interrogation of genes recurrently mutated in DLBCL. Using a backbone of BCL2 with either BCL6 or MYC, we identify co-operating genetic alterations that promote growth or even full transformation into synthetically engineered DLBCL models. The resulting tumors can be expanded and sequentially transplanted in vivo, providing a scalable platform to test putative cancer genes and to create mutation-directed, bespoke lymphoma models.

Description

Keywords

Article, /631/67/70, /631/67/2329, /13/31, /13/106, /13/107, /13/109, /13/51, /14, /38, /38/23, /38/77, /38/91, /96, article

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723

Volume Title

10

Publisher

Nature Publishing Group UK