Azanucleoside treatment leads to B cell leukemia in Rag1 deficient mice
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ABSTRACT:
PROVIDER: PRJNA1272830 | ENA |
REPOSITORIES: ENA
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Project description:5-Aza-4’-thio-2’-deoxycytidine (ATC) is an azanucleoside cytidine analog used in preclinical studies for solid tumors as a promising DNA methyltransferase 1 (DNMT1) inhibitor. Repeated treatment with ATC has previously been shown to result in acute lymphoblastic leukemia (ALL) of both B-cell and T-cell origin in mice. Herein, Rag1 knockout mice were treated with ATC to determine if ATC could be oncogenic in non-lymphoid cells. However, ATC treatment targeted early B progenitors and invariably led to B-lineage ALL, with a gene expression signature similar to human B cell precursor (BCP) ALL. Whole exome sequencing revealed numerous single base substitutions of cytosine, primarily C>G transversions at CpG dinucleotides, within genes important for BCP-ALL. Bisulfite sequencing and treatment with a non-covalent DNMT1 inhibitor indicated that methylated cytosines were preferred targets for mutagenesis. This study reveals that ATC exposure leads to both DNMT1 dependent and independent mutagenesis and provides a direct link from ATC exposure to complex mutation signature to malignant transformation
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Project description:Both immunodeficient and wild type NOD mice exhibit defects in control of early T-cell development in the thymus. We show that Rag1-deficient NOD mice fail to enforce both the b-selection checkpoint and an earlier T-cell commitment checkpoint, based on genome-wide genetic and transcriptome analyses. A major QTL peak for the checkpoint breakthrough phenotype mapped to the diabetes susceptibility Idd9/11 region, as confirmed by congenic mouse analysis. Genome-wide RNA deep-sequencing revealed two classes of differences between NOD and B6 Rag1-deficient thymocytes: first, effects of genetic background prior to breakthrough, and second, effects of the breakthrough itself. These genotypes differentially express numerous signal transduction genes, prominently tyrosine kinase and actin-binding genes, some located within QTL regions. Emerging NOD breakthrough cells depart from the expected DN3 phenotype by expressing many stem cell-associated proto-oncogenes, such as Lmo2, Hhex, Lyl1, and Kit which are normally repressed earlier, and by illegitimate activation of post-b-selection genes like Cd2, Cd5, and Cd4. Co-expression of stem cell and T-cell genes persists in thymic lymphoma cells that emerge with high penetrance in these mice. These results imply that NOD thymocytes have defects that can collapse regulatory boundaries at two early T-cell checkpoints, which may predispose them to leukemia and autoimmunity. Genetic and transcriptome analyses of early T-cell checkpoint failure and leukemia initiation in Rag1-deficient NOD mice
2013-03-07 | E-GEOD-40688 | biostudies-arrayexpress
Project description:Both immunodeficient and wild type NOD mice exhibit defects in control of early T-cell development in the thymus. We show that Rag1-deficient NOD mice fail to enforce both the b-selection checkpoint and an earlier T-cell commitment checkpoint, based on genome-wide genetic and transcriptome analyses. A major QTL peak for the checkpoint breakthrough phenotype mapped to the diabetes susceptibility Idd9/11 region, as confirmed by congenic mouse analysis. Genome-wide RNA deep-sequencing revealed two classes of differences between NOD and B6 Rag1-deficient thymocytes: first, effects of genetic background prior to breakthrough, and second, effects of the breakthrough itself. These genotypes differentially express numerous signal transduction genes, prominently tyrosine kinase and actin-binding genes, some located within QTL regions. Emerging NOD breakthrough cells depart from the expected DN3 phenotype by expressing many stem cell-associated proto-oncogenes, such as Lmo2, Hhex, Lyl1, and Kit which are normally repressed earlier, and by illegitimate activation of post-b-selection genes like Cd2, Cd5, and Cd4. Co-expression of stem cell and T-cell genes persists in thymic lymphoma cells that emerge with high penetrance in these mice. These results imply that NOD thymocytes have defects that can collapse regulatory boundaries at two early T-cell checkpoints, which may predispose them to leukemia and autoimmunity.
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Project description:To identify mechanisms that regulate V(D)J recombination, we used proximity-dependent biotin identification to analyze the interactomes of full length and truncated forms of RAG1 in pre-B cells. This revealed an association of RAG1 with numerous nucleolar proteins in a manner dependent on amino acids 216-383 and allowed identification of a motif required for nucleolar localization. Experiments in transformed pre-B cell lines and cultured primary pre-B cells reveal a strong correlation between disruption of nucleoli, reduced association of RAG1 with a nucleolar marker, and increases in V(D)J recombination activity. Mutation of the RAG1 nucleolar localization motif boosts recombination while removal of the first 215 amino acids of RAG1, which are required for efficient egress from nucleoli, reduces recombination activity. Our findings indicate that nucleolar sequestration of RAG1 is a negative regulatory mechanism in V(D)J recombination and identify regions of the RAG1 N-terminal region that control nucleolar association and egress.
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Project description:The RAG1/RAG2 endonuclease initiates V(D)J recombination at antigen receptor loci but also binds to thousands of places outside of these loci. RAG2 localizes directly to lysine 4 trimethylated histone 3 (H3K4me3) through a PHD finger. The relative contribution of RAG2-dependent and RAG1-intrinsic mechanisms in determining RAG1 binding patterns is not known. Through analysis of deep RAG1 ChIP-seq data, we provide a quantitative description of the forces underlying genome-wide targeting of RAG1. Surprisingly, sequence-specific DNA binding contributes minimally to RAG1 targeting outside of antigen receptor loci. Instead, RAG1 binding is driven by two distinct modes of interaction with chromatin: the first is driven by H3K4me3, promoter-focused, and dependent on the RAG2 PHD, and the second is defined by H3K27Ac, enhancer-focused, and dependent on "non-core" portions of RAG1. Based on this and additional chromatin and genomic features, we formulated a predictive model of RAG1 targeting to the genome. RAG1 binding sites predicted by our model correlate well with observed patterns of RAG1-mediated breaks in human pro-B acute lymphoblastic leukemia. Overall, this study provides an integrative model for RAG1 genome-wide binding and off-target activity, and reveals a novel role for the RAG1 non-core region in RAG1 targeting.
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Project description:The lung is constantly exposed to potentially pathogenic particles and microorganisms. It has recently become evident that not only innate, but also adaptive immune responses to particulates such as crystalline silica (SiO2) entering the respiratory tract are complex and dynamic events. Although the cellular mechanisms and anatomical consequences involved in the development of silicosis have been extensively studied, they still remain poorly understood. Based on their capacity for immune regulation, lymphocytes may play a role in determining the respiratory response to environmental challenge by SiO2. The objective of this study was to characterize the impact of SiO2 exposure on respiratory immune processes, with particular emphasis on evaluating the importance of lymphocytes in the murine silicosis model. Therefore, we utilized lymphopenic mice including NK deficient, Rag1-/- or a combination (Rag1-/- NK depleted) and demonstrated that SiO2-induced fibrosis and inflammation occur independently of T, B, NK T, and NK cells. Studies in Rag1-/- mice further suggest that lymphocytes may participate in controlling SiO2-induced inflammation through modulation of the Nalp3 inflammasome. This observation may have clinical relevance in the treatment of inflammatory and fibrotic lung diseases that are either refractory or respond sub-optimally to current therapeutics.
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