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A rapid embryonic stem cell-based mouse model for B-cell lymphomas driven by Epstein-Barr virus protein LMP1

Item Type:Article
Title:A rapid embryonic stem cell-based mouse model for B-cell lymphomas driven by Epstein-Barr virus protein LMP1
Creators Name:Ba, Z. and Meng, F.L. and Gostissa, M. and Huang, P.Y. and Ke, Q. and Wang, Z. and Dao, M.N. and Fujiwara, Y. and Rajewsky, K. and Zhang, B. and Alt, F.W.
Abstract:The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) contributes to oncogenic human B-cell transformation. Mouse B cells conditionally expressing LMP1 are not predisposed to B-cell malignancies, as LMP1-expressing B cells are eliminated by T cells. However, mice with conditional B-cell LMP1 expression and genetic elimination of alpha/beta and gamma/delta T cells ("CLT" mice) die early in association with B-cell lymphoproliferation and lymphomagenesis. Generation of CLT mice involves in-breeding multiple independently segregating alleles. Thus, although introduction of additional activating or knockout mutations into the CLT model is desirable for further B-cell expansion and immunosurveillance studies, doing such experiments by germline breeding is time-consuming, expensive, and sometimes unfeasible. To generate a more tractable model, we generated clonal CLT embryonic stem (ES) cells from CLT embryos and injected them into RAG2-deficient blastocysts to generate chimeric mice, which, like germline CLT mice, harbor splenic CLT B cells and lack T cells. CLT chimeric mice generated by this RAG2-deficient blastocyst complementation ("RDBC") approach die rapidly in association with B-cell lymphoproliferation and lymphoma. Because CLT lymphomas routinely express the activation-induced cytidine deaminase (AID) antibody diversifier, we tested potential AID roles by eliminating the AID gene in CLT ES cells and testing them via RDBC. We found that CLT and AID-deficient CLT ES chimeras had indistinguishable phenotypes, showing that AID is not essential for LMP1-induced lymphomagenesis. Beyond expanding accessibility and utility of CLT mice as a cancer immunotherapy model, our studies provide a new approach for facilitating generation of genetically complex mouse cancer models.
Keywords:Animal Disease Models, Antigen T-Cell Receptors, B-Cell Lymphoma, Cell Line, DNA-Binding Proteins, Embryonic Stem Cells, Gene Knockout Techniques, Gene Targeting, Genetic Loci, Genotype, Immunologic Surveillance, Immunophenotyping, Knockout Mice, Viral Cell Transformation, Viral Matrix Proteins, Animals, Mice
Source:Cancer Immunology Research
ISSN:2326-6066
Publisher:American Association for Cancer Research (U.S.A.)
Volume:3
Number:6
Page Range:641-649
Date:June 2015
Official Publication:https://doi.org/10.1158/2326-6066.CIR-15-0058
PubMed:View item in PubMed

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