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T cell receptor dependent transformation of mature memory phenotype T cells

ABSTRACT: A fundamental goal in cancer research is identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth as this has the potential to reveal features that can be exploited therapeutically. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies but are unlikely to underlie initiation of mature lymphoid neoplasms, the cellular origin of which remains unclear. Here, we used a conditional Snf5 model to investigate the origin of peripheral T cell lymphomas. We find that the cell of origin is a mature CD44hiCD122lo CD8 T cell that resembles a subset of memory cells, a population with capacities for self-renewal and robust expansion - features shared with stem cells. We elucidate mechanism by showing that Snf5 loss leads to activation of a Myc network and stem cell transcriptional program. Finally, we demonstrate that lymphomagenesis depends upon TCR signaling, establishing a new paradigm for lymphomagenesis. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells is associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE29732 | GEO | 2011/11/01

SECONDARY ACCESSION(S): PRJNA141151

REPOSITORIES: GEO

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T cell receptor dependent transformation of mature memory phenotype T cells

Project description:A fundamental goal in cancer research is identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth as this has the potential to reveal features that can be exploited therapeutically. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies but are unlikely to underlie initiation of mature lymphoid neoplasms, the cellular origin of which remains unclear. Here, we used a conditional Snf5 model to investigate the origin of peripheral T cell lymphomas. We find that the cell of origin is a mature CD44hiCD122lo CD8 T cell that resembles a subset of memory cells, a population with capacities for self-renewal and robust expansion - features shared with stem cells. We elucidate mechanism by showing that Snf5 loss leads to activation of a Myc network and stem cell transcriptional program. Finally, we demonstrate that lymphomagenesis depends upon TCR signaling, establishing a new paradigm for lymphomagenesis. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells is associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers. Stable mouse Snf5-deficient T cell lymphoma cell lines were established. CD44hi and CD44lo subpopulations were purified and used to evaluate gene expression pattern in these two subpopulations. RNA was isolated from each of these samples and used for gene expression profiling on Affymetrix 430A arrays.

2011-11-01 | E-GEOD-29732 | biostudies-arrayexpress

Monoclonal Antibody Therapy Before Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoid Malignancies

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Project description:Peripheral T-cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcome.T-cell receptor (TCR) is emerging as a key driver of T lymphocytes transformation. However, the role of chronic TCR activation in lymphomagenesis and in survival of lymphoma cells is still poorly understood. Using an original mouse model, we report here that chronic TCR stimulation drives T-cell lymphomagenesis whereas TCR signaling does not contribute to PTCL survival. Transcriptome analyses of mouse PTCLs revealed a NK-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and Syk.

2021-05-11 | GSE174257 | GEO

ATAC-seq data from murine peripheral T-cell lymphoma and control normal T cells, NKT cells and NK cells

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Epigenetic antagonism between Snf5 and Ezh2 during oncogenic transformation

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NPMâ??ALK permits the survival of thymic T cells with aberrant T cell receptor rearrangements enabling thymic escape and tumor development

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Rad21-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation

Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.

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Human hematopoietic stem cell expansion through modulation of lineage-associated gene expression programs

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Elevated levels of H3K27me3 in Snf5-deficient cells

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Epigenetic antagonism between Snf5 and Ezh2 during oncogenic transformation

2010-10-19 | GSE23656 | GEO