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

Author

Listed:
  • Yexuan Deng

    (Nanjing University
    The Walter and Eliza Hall Institute of Medical Research)

  • Sarah T. Diepstraten

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Margaret A. Potts

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Göknur Giner

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Stephanie Trezise

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ashley P. Ng

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Gerry Healey

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Serena R. Kane

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Amali Cooray

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kira Behrens

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Amy Heidersbach

    (Genentech, Inc.)

  • Andrew J. Kueh

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Martin Pal

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Charles Sturt University)

  • Stephen Wilcox

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Lin Tai

    (The Walter and Eliza Hall Institute of Medical Research)

  • Warren S. Alexander

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jane E. Visvader

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Stephen L. Nutt

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Andreas Strasser

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Benjamin Haley

    (Genentech, Inc.)

  • Quan Zhao

    (Nanjing University)

  • Gemma L. Kelly

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Marco J. Herold

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

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.

Suggested Citation

  • 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. Kue, 2022. "Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32485-9
    DOI: 10.1038/s41467-022-32485-9
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    References listed on IDEAS

    as
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