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 Haley, Quan Zhao, Gemma L. Kelly and Marco J. Herold ()
Additional contact information
Yexuan Deng: Nanjing University
Sarah T. Diepstraten: The Walter and Eliza Hall Institute of Medical Research
Margaret A. Potts: The Walter and Eliza Hall Institute of Medical Research
Göknur Giner: The Walter and Eliza Hall Institute of Medical Research
Stephanie Trezise: The Walter and Eliza Hall Institute of Medical Research
Ashley P. Ng: The Walter and Eliza Hall Institute of Medical Research
Gerry Healey: The Walter and Eliza Hall Institute of Medical Research
Serena R. Kane: The Walter and Eliza Hall Institute of Medical Research
Amali Cooray: The Walter and Eliza Hall Institute of Medical Research
Kira Behrens: The Walter and Eliza Hall Institute of Medical Research
Amy Heidersbach: Genentech, Inc.
Andrew J. Kueh: The Walter and Eliza Hall Institute of Medical Research
Martin Pal: The Walter and Eliza Hall Institute of Medical Research
Stephen Wilcox: The Walter and Eliza Hall Institute of Medical Research
Lin Tai: The Walter and Eliza Hall Institute of Medical Research
Warren S. Alexander: The Walter and Eliza Hall Institute of Medical Research
Jane E. Visvader: The Walter and Eliza Hall Institute of Medical Research
Stephen L. Nutt: The Walter and Eliza Hall Institute of Medical Research
Andreas Strasser: The Walter and Eliza Hall Institute of Medical Research
Benjamin Haley: Genentech, Inc.
Quan Zhao: Nanjing University
Gemma L. Kelly: The Walter and Eliza Hall Institute of Medical Research
Marco J. Herold: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32485-9

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