Journal article
Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance
Y Deng, ST Diepstraten, MA Potts, G Giner, S Trezise, AP Ng, G Healey, SR Kane, A Cooray, K Behrens, A Heidersbach, AJ Kueh, M Pal, S Wilcox, L Tai, WS Alexander, JE Visvader, SL Nutt, A Strasser, B Haley Show all
Nature Communications | Published : 2022
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 lym..
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Awarded by Victorian Cancer Agency
Funding Acknowledgements
We thank C Gatt, C Epifanio and G Siciliano for expert animal care; B Helbert and K Mackwell for genotyping; S Monard and his team for help with flow cytometry; MA Anderson and D Hilton for insightful discussions and all the members of the Herold and Kelly laboratories. This work was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) (Project Grants 1159658, 1186575 and 1145728 to M.J.H., 1143105 to M.J.H. and A.S., 1144905 to S.L.N., Ideas Grants 2002618 and 2001201 to G.L.K., Program Grant 1113133 to A.S. and J.E.V., 1113577 to W.S.A., Fellowships 1058344 to W.S.A., 1102742 to J.E.V., 1020363 to A.S., 1156095 to M.J.H. and Investigator Grant 1173342 to W.S.A.), the Leukemia and Lymphoma Society of America (LLS SCOR 7015-18 to A.S., G.L.K., M.J.H.), the Cancer Council of Victoria (project grant 1147328 and 2021 Grant In Aid to M.J.H., 1052309 to A.S., 1147328 to G.L.K. and Venture Grant to M.J.H. and A.S.), Victorian Cancer Agency (MCRF Fellowship 17028 to G.L.K., Leukaemia Foundation of Australia (grant to A.S. and G.L.K.), Phenomics Australia (to A.J.K. and M.J.H.) the estate of Anthony (Toni) Redstone OAM (A.S. and G.L.K.), the Craig Perkins Cancer Research Foundation (G.L.K.), the Dyson Bequest (G.L.K.), the Harry Secomb Trust (G.L.K.) as well as by operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (361646 and 9000220) and the Victorian State Government Operational Infrastructure Support Program.