Mice transgenic for human CTLA4-CD28 fusion gene develop adult T cell leukemia/lymphoma-like lymphoma
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ABSTRACT:
PROVIDER: PRJNA675285 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13004213_1.fastq.gz | Fastqsanger.gz | |||
| SRR13004213_2.fastq.gz | Fastqsanger.gz | |||
| SRR13004214_1.fastq.gz | Fastqsanger.gz | |||
| SRR13004214_2.fastq.gz | Fastqsanger.gz | |||
| SRR13004215_1.fastq.gz | Fastqsanger.gz |
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Project description:CTLA4-CD28 gene fusion has been reported to occur in diverse types of T-cell lymphoma. The fusion event is expected to convert inhibitory signals to activating signals promoting proliferation and potentially transformation of T-cells. To test the function of the CTLA4-CD28 fusion gene in vivo, we generated a murine model that expresses the gene in a T-cell specific manner. The transgenic mice show shorter life spans and inflammatory responses including lymphadenopathy and splenomegaly. T-cells show higher levels of activation and infiltrate various organs including skin and lung. T-cells, in particular CD4+ helper T-cells, were also readily transplanted to immunocompromised mice. Transcriptomic profiling revealed that the gene expression pattern in CD4+ cells most closely resembles that of adult T cell leukemia/lymphoma (ATLL). Consistently, we detected supernumerary Foxp3+ cells in transgenic and transplanted mice. This is the first report demonstrating the transforming activity of the CTLA4-CD28 fusion gene in vivo, and this murine model should be useful in dissecting the molecular events subsequent to the mutation in ATLL.
2022-01-01 | GSE161035 | GEO
Project description:During activation, T cells integrate multiple signals from APCs and cytokine milieu. The blockade of these signals can have clinical benefits as exemplified by CTLA4-Ig, which blocks interaction of B7 co-stimulatory molecules on APCs with CD28 on T cells. Variants of CTLA4-Ig, abatacept and belatacept are FDA approved as immunosuppressive agents in arthritis and transplantation whereas murine studies suggested that CTLA4-Ig can be beneficial in a number of other diseases. However, detailed analysis of human CD4 cell hyporesponsivness induced by CTLA4-Ig has not been performed. Herein, we established a model to study effect of CTLA4-Ig on the activation of human naM-CM-/ve T cells in a human mixed lymphocytes system. Comparison of human CD4 cells activated in the presence or absence of CTLA4-Ig, showed that co-stimulation blockade during TCR activation does not affect NFAT signaling but results in decreased activation of NF-kB and AP-1 transcription factors followed by profound decrease in proliferation and cytokine production. The resulting T cells become hyporesponsive to secondary activation and, although capable of receiving TCR signals, fail to proliferate or produce cytokines, demonstrating properties of anergic cells. However, unlike some models of T cell anergy, these cells did not possess increased levels of TCR signaling inhibitor CBLB. Rather, the CTLA4-Ig induced hyporesponsiveness was associated with an elevated level of p27kip1 cyclin-dependent kinase inhibitor. Time series. Human resting and activated T cell dUTP mRNA-Seq profiles were generated on Illumina HiSeq2500
2015-02-17 | E-GEOD-64712 | biostudies-arrayexpress
Project description:During activation, T cells integrate multiple signals from APCs and cytokine milieu. The blockade of these signals can have clinical benefits as exemplified by CTLA4-Ig, which blocks interaction of B7 co-stimulatory molecules on APCs with CD28 on T cells. Variants of CTLA4-Ig, abatacept and belatacept are FDA approved as immunosuppressive agents in arthritis and transplantation whereas murine studies suggested that CTLA4-Ig can be beneficial in a number of other diseases. However, detailed analysis of human CD4 cell hyporesponsivness induced by CTLA4-Ig has not been performed. Herein, we established a model to study effect of CTLA4-Ig on the activation of human naïve T cells in a human mixed lymphocytes system. Comparison of human CD4 cells activated in the presence or absence of CTLA4-Ig, showed that co-stimulation blockade during TCR activation does not affect NFAT signaling but results in decreased activation of NF-kB and AP-1 transcription factors followed by profound decrease in proliferation and cytokine production. The resulting T cells become hyporesponsive to secondary activation and, although capable of receiving TCR signals, fail to proliferate or produce cytokines, demonstrating properties of anergic cells. However, unlike some models of T cell anergy, these cells did not possess increased levels of TCR signaling inhibitor CBLB. Rather, the CTLA4-Ig induced hyporesponsiveness was associated with an elevated level of p27kip1 cyclin-dependent kinase inhibitor.
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Project description:Matching molecularly targeted therapies with cancer subtype-specific gene mutations is revolutionizing oncology care. However, for rare cancers this approach is problematic due to the often poor understanding of the disease's natural history and phenotypic heterogeneity, making treatment of these cancers a particularly unmet medical need in clinical oncology. Advanced Sézary syndrome (SS), an aggressive, exceedingly rare variant of cutaneous T-cell lymphoma (CTCL) is a prototypical example of a rare cancer. Through whole genome and RNA sequencing (RNA-seq) of a SS patient's tumor we discovered a highly expressed gene fusion between CTLA4 (cytotoxic T lymphocyte antigen 4) and CD28 (cluster of differentiation 28), predicting a novel stimulatory molecule on the surface of tumor T cells. Treatment with the CTLA4 inhibitor ipilimumab resulted in a rapid clinical response. Our findings suggest a novel driver mechanism for SS, and cancer in general, and exemplify an emerging model of cancer treatment using exploratory genomic analysis to identify a personally targeted treatment option when conventional therapies are exhausted.
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Project description:CTLA4-CD28 gene fusion has been reported to occur in diverse types of T cell lymphoma. The fusion event is expected to convert inhibitory signals to activating signals and promote proliferation and potentially transformation of T cells. To test the function of the CTLA4-CD28 fusion gene in vivo, we generated a murine model that expresses the gene in a T cell-specific manner. The transgenic mice have shorter life spans and display inflammatory responses including lymphadenopathy and splenomegaly. T cells in turn show higher levels of activation and infiltrate various organs including the lung and skin. T cells, in particular CD4+ helper T cells, were also readily transplantable to immunocompromised mice. Transcriptomic profiling revealed that the gene expression pattern in CD4 + T cells closely resembles that of adult T cell leukemia/lymphoma (ATLL) and that of angioimmunoblastic T cell lymphoma (AITL) tissues. Consistently, we detected supernumerary FOXP3+ cells and PD-1+ cells in transgenic and transplanted mice. This is the first report demonstrating the transforming activity of the CTLA4-CD28 fusion gene in vivo, and this murine model should be useful in dissecting the molecular events downstream to this mutation.
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Project description:Ctla4-/- mice suffer from a severe autoimmunity characterized by indiscriminate self-reactive T cell activation. Itk-/-Ctla4-/- (DKO) mice are protected from lethal autoimmunity despite a fulminant autoimmune process in the LNs as self-reative T cells fail to migrate to destroy tissues. We used microarray to identify underlying differences in gene expression that could account for lack of migration of DKO T cells into tissues. CD4+CD25neg T cells from 3 weeks old male Ctla4-/- or DKO mice were sorted in duplicates, RNA was extracted using TRIzol reagent and microarray analysis performed with the Affymetrix MoGene 1.0 ST array
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Project description:We used gene expression data from Eµ-myc mouse lymphomas to perform unsupervised analyses that identified two lymphoma subgroups. We also used this data to develop a genomic signature to classify new lymphomas. When Eµ-myc mice had evidence of lymphoma and/or ill appearance, they were humanely sacrificed and dissected. Lymphoma tissue was obtained and flash frozen in liquid nitrogen. Later, lymphoma tissue was homogenized, and RNA was extracted. Gene expression microarrays were performed with the isolated RNA.
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Project description:We used gene expression data from Eµ-myc mouse lymphomas to perform unsupervised analyses that identified two lymphoma subgroups. We also used this data to develop a genomic signature to classify new lymphomas.
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Project description:The major goal of this experiment was to identify the overall changes in gene expression of human CD4+CD28 null T-cells that develop after repetitive [xeno] antigen stimulation, in comparison to normal CD4+CD28+ T-cells. These cells were derived by adoptive transfer of human CD4 T-cells from a normal donor (all CD28+) into immunodeficient mice.
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