Medical Biology - Research Publications

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Author: Herold, Marco × Author: Kelly, Gemma × Author: Strasser, Andreas × End date: 2022 × Start date: 2020 ×

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    Loss of TRP53 reduces but does not overcome dependency of lymphoma cells on MCL-1
    Aubrey, BJ ; Brennan, MS ; Diepstraten, ST ; Wang, Z ; Chang, C ; Herold, MJ ; Strasser, A ; Kelly, GL (SPRINGERNATURE, 2022-05)
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    Generation of a CRISPR activationmouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance (vol 13, 4739, 2022)
    Deng, Y ; Diepstraten, ST ; Potts, MA ; Giner, G ; Trezise, S ; Ng, AP ; Healey, G ; Kane, SR ; Cooray, A ; Behrens, K ; Heidersbach, A ; Kueh, AJ ; Pal, M ; Wilcox, S ; Tai, L ; Alexander, WS ; Visvader, JE ; Nutt, SL ; Strasser, A ; Haley, B ; Zhao, Q ; Kelly, GL ; Herold, MJ (NATURE PORTFOLIO, 2022-08-25)
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    Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance
    Deng, Y ; Diepstraten, ST ; Potts, MA ; Giner, G ; Trezise, S ; Ng, AP ; Healey, G ; Kane, SR ; Cooray, A ; Behrens, K ; Heidersbach, A ; Kueh, AJ ; Pal, M ; Wilcox, S ; Tai, L ; Alexander, WS ; Visvader, JE ; Nutt, SL ; Strasser, A ; Haley, B ; Zhao, Q ; Kelly, GL ; Herold, MJ (NATURE PORTFOLIO, 2022-08-12)
    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.