CXCR5 Antagonist in Angioimmunoblastic T-cell Lymphoma
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE191119 | GEO | 2022/12/15
REPOSITORIES: GEO
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Project description:A missense mutation in RHOA encoding p.Gly17Val has been reported to occur frequently in angioimmunoblastic T-cell lymphoma (AITL). Here, we describe a murine model which expresses the human RHOA mutant gene product in a T-cell specific manner and develops AITL-like symptoms. Most transgenic mice feature with latency one or two enlarged lymph nodes characterized by aberrant lymph node architecture, extensive lymphocytic infiltration, extrafollicular meshwork of follicular dendritic cells (FDC) and arborized endothelial venules. We also provide evidence for presence of dominant T cell clonal populations and expansion of B-cells leading to hypergammaglobulinemia. Transcriptomic profiling revealed that the gene expression pattern within affected lymph nodes of the mice most closely resembles that of AITL patients with the identical p.Gly17Val mutation. The murine model should therefore be useful in dissecting pathogenesis of AITL at the molecular level and in preclinical trials of various therapeutic agents, particularly for the cases with the highly prevalent p.Gly17Val mutation.
2020-06-08 | GSE115510 | GEO
Project description:Background: Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in need of new more specific therapeutic regimen. The drivers of malignancy in this disease are CD4+ follicular helper T cells (Tfh). The metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requirements with the objective to propose a novel therapeutic option. Methods: To reveal the prominent metabolic pathways used by the AITL lymphoma cells, leveraged on our previously established AITL mouse model by crossing metabolomic and proteomic data of murine AITL cells. We confirmed these results using AITL patient and healthy T cell expression data. Results: Strikingly, the mAITL Tfh cells were highly dependent on the second branch of the Kennedy pathway, the choline lipid pathway, responsible for the production of the major membrane constituent phosphatidylcholine. Moreover, gene expression data from Tfh cells isolated from AITL patient tumors, confirmed the upregulation of the choline lipid pathway. Several enzymes involved in this pathway such as choline kinase, catalyzing the first step in the phosphatidylcholine pathway, respectively, are upregulated in multiple tumors other than AITL. Here we showed that treatment of our mAITL preclinical mouse model with the fatty acid oxydation inhibitor, etomoxir, significantly increased their survival and even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti-tumor cells. Specific inhibition of Chok confirmed the importance of the phosphatidylcholine production pathway in the neoplastic CD4+ T cells, since it irradicated almost all the mAITL Tfh cells from the tumors. Finally, the same inhibitor induced in human AITL lymphoma biopsies cell death of the majority of the hAITL PD-1high neoplastic cells. Conclusion: Our results suggest that interfering with the choline metabolism in AITL might represent a new therapeutic strategy for these patients.
2024-04-04 | PXD046786 | Pride
Project description:Angioimmunoblastic T-Cell lymphoma (AITL) is a mature T-cell lymphoma of blood or lymph vessel immunoblasts. It is the most common subtype of T-cell lymphoma in the Western world and the second most frequent one in Asia. We sequenced nine pairs of AITL exomes and their matched normals. Frequent mutations in TET2 and RHOA were detected, and confirmed through targeted sequencing in a larger cohort of 43 samples. Gene expression profiling was performed to identify genes differentially expressed between patients with and without mutations in genes of interest.
2018-09-14 | GSE51521 | GEO
Project description:Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma that originates from T follicular helper (Tfh) cells and is characterized by a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL but their contribution to tumorigenesis is poorly understood. We have developed an AITL mouse model that is driven by Idh2 and Tet2 mutations and in which Tfh cells exhibit aberrant transcriptomic and epigenetic programming. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered crosstalk with normal germinal center B cells that promotes B clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. This altered Tfh-B cell communication could explain the unique relationship between Idh2 mutation and the prototypical AITL TME. Our mouse model also recapitulates important features of human IDH2-mutated AITL, providing a rationale for exploring the therapeutic targeting of Tfh-TME crosstalk for AITL treatment.
2023-02-01 | GSE221602 | GEO
Project description:Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma that originates from T follicular helper (Tfh) cells and is characterized by a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL but their contribution to tumorigenesis is poorly understood. We have developed an AITL mouse model that is driven by Idh2 and Tet2 mutations and in which Tfh cells exhibit aberrant transcriptomic and epigenetic programming. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered crosstalk with normal germinal center B cells that promotes B clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. This altered Tfh-B cell communication could explain the unique relationship between Idh2 mutation and the prototypical AITL TME. Our mouse model also recapitulates important features of human IDH2-mutated AITL, providing a rationale for exploring the therapeutic targeting of Tfh-TME crosstalk for AITL treatment.
2023-02-01 | GSE221604 | GEO
Project description:We demonstrate that CXCR5+CD8+ T cells are a distinct human T-cell subset that homes to follicles and exerts strong antitumor activity compared with CXCR5-CD8+ T cells. Importantly, this subset is associated with improved outcome in follicular lymphoma patients.
2020-09-02 | GSE105095 | GEO
Project description:Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma that originates from T follicular helper (Tfh) cells and is characterized by a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL but their contribution to tumorigenesis is poorly understood. We have developed an AITL mouse model that is driven by Idh2 and Tet2 mutations and in which Tfh cells exhibit aberrant transcriptomic and epigenetic programming. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered crosstalk with normal germinal center B cells that promotes B clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. This altered Tfh-B cell communication could explain the unique relationship between Idh2 mutation and the prototypical AITL TME. Our mouse model also recapitulates important features of human IDH2-mutated AITL, providing a rationale for exploring the therapeutic targeting of Tfh-TME crosstalk for AITL treatment.
2023-02-01 | GSE221600 | GEO
Project description:Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma that originates from T follicular helper (Tfh) cells and is characterized by a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL but their contribution to tumorigenesis is poorly understood. We have developed an AITL mouse model that is driven by Idh2 and Tet2 mutations and in which Tfh cells exhibit aberrant transcriptomic and epigenetic programming. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered crosstalk with normal germinal center B cells that promotes B clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. This altered Tfh-B cell communication could explain the unique relationship between Idh2 mutation and the prototypical AITL TME. Our mouse model also recapitulates important features of human IDH2-mutated AITL, providing a rationale for exploring the therapeutic targeting of Tfh-TME crosstalk for AITL treatment.
2023-02-01 | GSE221599 | GEO
Project description:Glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) is emerging as a key player in T-cell development, function and cancer. Here we investigated the role of GAPDH in T-cell development/function by overexpressing GAPDH in the T-cell lineage. Aged mice developed: 1) splenomegaly, 2) enlarged lymph nodes, 3) lymphocyte-infiltrations in the liver and bone marrow. All showed an increase of strongly proliferating and clonal Tfh CXCR5+PD1highCD4+-T cells associated with germinal center B cells and inflammatory cytokine-release. Gene-set-expression-analysis confirmed that this lymphoma was equivalent to human angioimmunoblastic T-cell lymphoma (AITL). Mechanistically, GAPDH induced NF-kB pathway in the murine AITL in vivo inhibition of NF-kB combined with anti-PD1 increased mice survival and cancer immune response. GAPDH-dependent modulation of NF-kB in T-cells allowed to model AITL-disease and evaluate treatments.
2021-10-20 | GSE121592 | GEO
Project description:AITL usually consists of a small population of malignant T cells extensively infiltrated by multiple lineages of other immune cells. It is challenging to characterize the tumour cells with traditional histopathology or next-generation sequencing technique using bulk tumour. However, the recent advances in single-cell sequencing technologies have enabled scientists to dissect cellular heterogeneity and gain new insights into cell origins and tumorigenesis of various hematologic malignancy5-8. In this study, we holistically analysis a typical case of AITL tumour using single-cell profiling, including CITE-Seq and immune repertoire sequencing on the same cell. The integration analysis revealed that the neoplastic cells are more similar to CD8+ cytotoxic T cells instead of Tfh cells. Moreover, we further confirmed that GAPDH-activated NFκB pathway was the key driver pathway on tumorigenesis.
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