Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Study of the microenvironment of angioimmunoblastic T-cell lymphoma

ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2 mutations, whereas the G17V RHOA mutation in immature cells with TET2 mutations promotes development of T follicular helper-like tumor cells. We investigated the mechanism by which TET2-mutant immune cells enable AITL development. Single-cell RNA-sequencing of human AITL samples revealed significant expansion of aberrant B cells. The genes expressed in aberrantly expanded GCB cells in murine tumors were also broadly expressed in the B-lineage cells of TET2-mutant human AITL.

PROVIDER: EGAS00001006401 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Similar Datasets

Mouse model of RHOA G17V mutation in Peripheral T-Cell Lymphoma

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.

2018-10-01 | GSE83918 | GEO

Identify the key signaling pathway involved in the Tet2 deficiency-induced clonal hematopoiesis

Project description:To investigate the signaling pathway required for the Tet2 mutant associated clonal hematopoiesis, we identified the activated signaling pathway in Tet2-deficient hematopoietic stem/progenitor cells compared to WT cells and using transgentic mouse model to validate our findings. In short, the cGAS-STING pathway is activated in Tet2-deficient HSPCs and promotes the development of CH associated with Tet2 deficiency.

2023-05-15 | GSE232384 | GEO

Mutation Order Affects Tumor Evolution and Clinical Course of Disease

Project description:Background: Cancers result from accumulation of somatic mutations and their properties are thought to reflect the sum of these mutations. However, little is known about the consequences of altering the order of mutation acquisition. Methods: Mutation order was determined in myeloproliferative neoplasm patients by genotyping hematopoietic colonies or next generation sequencing. Stem and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. Results: Age of presentation, acquisition of JAK2V617F homozygosity and the balance of immature progenitors were all influenced by mutation order. Compared to TET2-first patients, JAK2-first patients had an increased likelihood of presenting with polycythemia vera than essential thrombocythemia, an increased risk of thrombosis and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. In studies of single hematopoietic stem and progenitor cells (HSPCs), mutation order influenced the proliferative response to JAK2V617F and the capacity of double-mutant HSPCs to generate colony-forming cells. Moreover the HSPC compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2/TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2V617F in a cell-intrinsic manner, and prevented JAK2V617F from up-regulating genes associated with proliferation. These data demonstrate that mutation order influences progenitor proliferation and terminal cell expansion, thus influencing clinical presentation, thrombosis risk and progenitor response to targeted therapy. Conclusions: The order in which JAK2 and TET2 mutations are acquired influences clinical features, stem/progenitor cell biology and clonal evolution in patients with myeloproliferative neoplasms.

2014-11-17 | E-MTAB-3086 | biostudies-arrayexpress

Tet2-mediated epigenetic programing of T follicular helper cell differentiation (RNA-Seq)

Project description:Tet2-mediated demethylation is a key component of epigenetic programing that promotes lineage specific gene expression and contributes to cellular differentiation and function. While the differentiation of CD4+ T cell subsets has been studied extensively, the epigenetic programs that regulate these processes remain unclear. We report that Tet2 acts to restrict the differentiation of T follicular helper (Tfh) cells in CD4+ T cells responding to viral infection. Tet2-deficient CD4+ T cells preferentially differentiated into highly functional germinal center (GC) Tfh cells that provided enhanced help for B cell responses. Using genome-wide expression and methylation analyses combined with Foxo1 ChIPseq analysis, we found that Tet2 coordinates with multiple transcription factors, including Foxo1, to mediate the demethylation and expression of their target genes following activation.

2022-06-15 | GSE183316 | GEO

Tet2-mediated epigenetic programing of T follicular helper cell differentiation (Methyl-Seq)

2022-06-15 | GSE182940 | GEO

Tet2-mediated epigenetic programing of T follicular helper cell differentiation (ChIP-Seq)

2022-06-15 | GSE183315 | GEO

Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

Project description:Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to Tet2 mutation. Cell differentiation stage also influenced Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitized cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.

1970-01-01 | MTBLS9914 | MetaboLights

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

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

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

2023-02-01 | GSE221599 | GEO

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

2023-02-01 | GSE221604 | GEO