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Angioimmunoblastic T-cell lymphoma-like lymphadenopathy in mice transgenic for human RHOA with p.Gly17Val mutation

ABSTRACT: Angioimmunoblastic T-cell lymphoma-like lymphadenopathy in mice transgenic for human RHOA with p.Gly17Val mutation

PROVIDER: PRJNA475242 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7280720_1.fastq.gz	Fastqsanger.gz
	SRR7280720_2.fastq.gz	Fastqsanger.gz
	SRR7280721_1.fastq.gz	Fastqsanger.gz
	SRR7280721_2.fastq.gz	Fastqsanger.gz
	SRR7280722_1.fastq.gz	Fastqsanger.gz

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Angioimmunoblastic T-cell lymphoma-like lymphadenopathy in mice transgenic for human RHOA with p.Gly17Val mutation

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.

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Project description:Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive lymphoid tumor derived from malignant transformation of T follicular helper (Tfh) cells. Genetically, AITL is characterized by loss of function mutations in the Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val, G17V) in the RHOA small GTPase gene Moreover, RHOA G17V expression in Tet2 deficient hematopoietic progenitors resulted in the specific development of lymphoid tumors resembling human AITL. Notably, inhibition of ICOS signaling impaired the growth of RHOA G17V-induced mouse lymphomas in vivo, thus providing a potential new rational approach for the treatment of AITL.

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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.

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TET2 loss and the lymphoma-associated RHOA mutation cooperate to disrupt CD4+ T cell function through inactivation of FOXO1

Project description:Angioimmunoblastic T cell lymphoma (AITL) represents a distinctive form of peripheral T cell lymphoma with a dismissal prognosis. Recent exome sequencing in AITL patients revealed frequent coexistence of somatic mutations in the RHO GTPase (RHOAG17V) and the 5-methylcytosine oxidase TET2. Here we demonstrated that Tet2 loss and RhoAG17V cooperatively caused abnormal CD4+ T cell proliferation and differentiation by perturbing FoxO1 gene expression and its subcellular localization, an abnormality that is also detected in AITL tumor samples. Re-expression of FoxO1 attenuated aberrant immune responses induced by genetic lesions in both Tet2 and RhoA. Our findings suggest that mutational cooperativity between epigenetic factors and GTPases in adult CD4+ T cells may account for immunoinflammatory responses that are commonly associated with AITL.

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Angioimmunoblastic T-cell lymphoma-like lymphadenopathy in mice transgenic for human <i>RHOA</i> with p.Gly17Val mutation.

Project description:A missense mutation in RHOA encoding p.Gly17 Val 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. Importantly, we provide evidence for expansion of PD-1+ follicular helper T (Tfh) cells which are the neoplastic cells of AITL. In addition, we saw proliferation of B-cells leading to hypergammaglobulinemia and the presence of dominant T cell clonal populations. Transplantation of lymph node cells to immunocompromised mice partly recreated lymphadenopathy after a long latency and with low penetrance suggesting that cells have undergone partial transformation to a premalignant state. Transcriptomic profiling revealed that the gene expression pattern within affected lymph nodes of the mice closely resembles that of AITL patients with the identical RHOA p.Gly17 Val mutation. The murine model should, therefore, be useful in dissecting pathogenesis of AITL at the molecular level particularly for the cases with the RHOA p.Gly17Val mutation.

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Synergy between IDH2 and TET2 mutations modulates Tfh cell functional interaction with the angioimmunoblastic T-cell lymphoma microenvironment [Bisulfite-seq]

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