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A novel CRISPR activation mouse enables modelling of aggressive lymphoma and interrogation of venetoclax resistance

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/+ 38 ) for inducing gene expression in vivo and in vitro. Using dCas9a-SAMKI 39 primary lymphocytes, we induced 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 transactivated pro-survival BCL-2 in Eµ-MycT/+;dCas9a-SAMKI/+ 42 haematopoietic stem and progenitor cells. Mice transplanted with these cells rapidly developed lymphomas expressing high BCL-2 and MYC. Unlike standard Eµ-Myc lymphomas, BCL-2 expressing lymphomas were highly sensitive to the BCL-2 inhibitor venetoclax. We performed genome-wide activation screens in these lymphoma cells and found a dominant role for the BCL-2 protein A1 in venetoclax resistance. Here we show the power of our CRISPRa model for mimicking disease and providing insights into resistance mechanisms towards targeted therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE205509 | GEO | 2022/07/08

REPOSITORIES: GEO

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