Nature communications · 2022
Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Deng Yexuan, Diepstraten Sarah T, Potts Margaret A, Giner Göknur, Trezise Stephanie, Ng Ashley P, Healey Gerry, Kane Serena R, Cooray Amali, Behrens Kira, Heidersbach Amy, Kueh Andrew J, Pal Martin, Wilcox Stephen, Tai Lin, Alexander Warren S, Visvader Jane E, Nutt Stephen L, Strasser Andreas, Haley Benjamin, Zhao Quan, Kelly Gemma L, Herold Marco J
Аннотация
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.