Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance

Yexuan Deng, Sarah T. Diepstraten, Margaret A. Potts, Göknur Giner, Stephanie Trezise, Ashley P. Ng, Gerry Healey, Serena R. Kane, Amali Cooray, Kira Behrens, Amy Heidersbach, Andrew J. Kueh, Martin Pal, Stephen Wilcox, Lin Tai, Warren S. Alexander, Jane E. Visvader, Stephen L. Nutt, Andreas Strasser, Benjamin HaleyQuan Zhao, Gemma L. Kelly, Marco J. Herold

Research output: Contribution to journalArticlepeer-review

Abstract

CRISPR technologies have advanced cancer modelling in mice, but CRISPR activation (CRISPRa) methods have not been exploited in this context. We establish a CRISPRa mouse (dCas9a-SAMKI) for inducing gene expression in vivo and in vitro. Using dCas9a-SAMKI primary lymphocytes, we induce B cell restricted genes in T cells and vice versa, demonstrating the power of this system. There are limited models of aggressive double hit lymphoma. Therefore, we transactivate pro-survival BCL-2 in Eµ-MycT/+;dCas9a-SAMKI/+ haematopoietic stem and progenitor cells. Mice transplanted with these cells rapidly develop lymphomas expressing high BCL-2 and MYC. Unlike standard Eµ-Myc lymphomas, BCL-2 expressing lymphomas are highly sensitive to the BCL-2 inhibitor venetoclax. We perform genome-wide activation screens in these lymphoma cells and find a dominant role for the BCL-2 protein A1 in venetoclax resistance. Here we show the potential of our CRISPRa model for mimicking disease and providing insights into resistance mechanisms towards targeted therapies.

Original languageEnglish
Article number4739
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022

Fingerprint

Dive into the research topics of 'Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance'. Together they form a unique fingerprint.

Cite this