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

Author(s): 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;
Details: Publication Year 2022-08-12,Volume 13,Issue #1,Page 4739
Journal Title: Nature Communications
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-SAM(KI)) for inducing gene expression in vivo and in vitro. Using dCas9a-SAM(KI) 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-Myc(T/+);dCas9a-SAM(KI/+) 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.
Publisher: NPG
Research Division(s): Bioinformatics; Immunology; Advanced Technology And Biology; Blood Cells And Blood Cancer; Cancer Biology And Stem Cells
PubMed ID: 35961968
Publisher's Version: https://doi.org/10.1038/s41467-022-32485-9
Open Access at Publisher's Site: https://doi.org/0.1038/s41467-022-32485-9
NHMRC Grants: NHMRC/1145728, NHMRC/1143105, NHMRC/1144905, NHMRC/2002618, NHMRC/1113133, NHMRC/1113577, NHMRC/1058344, NHMRC/1020363,
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Creation Date: 2022-08-19 09:34:44

Last Modified: 2022-08-19 11:02:31