Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gene expression analysis of human CD8+ T cells treated with a DOT1L inhibitor

ABSTRACT: Adoptive T cell therapy (ACT) is a promising therapeutic approach for cancer patients. The use of allogeneic T cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. Through extensive chemical probe screening, we found that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviated allogeneic T cell responses. DOT1L inhibition with SGC0946 selectively ameliorated low-avidity T cell responses but not high-avidity antitumor T cell responses mediated by the high-affinity T cell receptor or chimeric antigen receptor. The inhibition of DOT1L in T cells prevented the development of graft-versus-host disease while retaining potent antitumor activity in xenogeneic ACT models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in ACT.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108694 | GEO | 2018/04/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Expression analysis of CD8+ T cells following high-avidity or low-avidity T cell receptor (TCR) stimulation in the presence or absence of a DOT1L inhibitor

Project description:Adoptive T cell therapy (ACT) is a promising therapeutic approach for cancer patients. The use of allogeneic T cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. T cell activation is finely regulated by multiple signaling molecules that are transcriptionally controlled by epigenetic mechanisms. Through extensive chemical probe screening, we found that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviated allogeneic T cell responses. DOT1L inhibition reduced miR-181a expression, which increased the ERK phosphatase DUSP6 expression. The inhibition of DOT1L or ectopic expression of DUSP6 in T cells prevented the development of graft-versus-host disease while retaining potent antitumor activity in multiple ACT models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in ACT. To further explore how DOT1L inhibition differentially affects high- and low-avidity stimulation-mediated T cell responses, gene expression profiles of DMF5- (high affinity) or cl.413- (low affinity) TCR-transduced T cells with or without SGC0946 treatment were analyzed following TCR stimulation.

2018-04-20 | GSE95038 | GEO

DOT1L protects neural stem cells from ER stress

Project description:In order to understand the role of H3K79me2 and DOT1L during CNS development, we analysed neural stem cells after pharmacological inhibition of DOT1L (5 µM SGC0946). To identify target genes of DOT1L in the cortex, we determined the transcriptome of cortical progenitor cells derived from E14.5 NMRI mice after interference with DOT1L activity for three days in vitro (DIV3). Therefore, three independent experiments were performed (ctrl1 – inh1, ctrl2 – inh2, ctrl3 – inh3).

2015-12-31 | E-MTAB-3521 | biostudies-arrayexpress

ChIPSeq of MV4;11 cell treated with DMSO, I-BET, SGC0946 and combination of I-BET and SGC0946

Project description:Central to the molecular pathogenesis of MLL leukaemia is the abnormal co-optation of members of transcription complexes including disrupter of telomeric silencing 1-like (DOT1L) and bromodomain containing protein 4 (BRD4). Consequently, targeted therapies against DOT1L and BRD4 are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukaemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation we find that native BRD4 and DOT1L exist in largely separate protein complexes. Genetic disruption or small molecule inhibition of BRD4 and DOT1L shows marked synergistic activity against MLL-FP leukaemia cell lines, primary human leukaemia cells and murine leukaemia models. Mechanistically, we find a previously unrecognised functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in close proximity to superenhancers. DOT1L via H3K79me2 facilitates the deposition of histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide novel insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this poor prognostic disease. ChIPSeq of MV4;11 cell treated with DMSO, I-BET, SGC0946 and combination of I-BET and SGC0946

2016-06-12 | E-GEOD-71776 | biostudies-arrayexpress

RNASeq of MV4;11 cell treated with DMSO, I-BET, SGC0946 and combination of I-BET and SGC0946

Project description:Central to the molecular pathogenesis of MLL leukaemia is the abnormal co-optation of members of transcription complexes including disrupter of telomeric silencing 1-like (DOT1L) and bromodomain containing protein 4 (BRD4). Consequently, targeted therapies against DOT1L and BRD4 are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukaemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation we find that native BRD4 and DOT1L exist in largely separate protein complexes. Genetic disruption or small molecule inhibition of BRD4 and DOT1L shows marked synergistic activity against MLL-FP leukaemia cell lines, primary human leukaemia cells and murine leukaemia models. Mechanistically, we find a previously unrecognised functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in close proximity to superenhancers. DOT1L via H3K79me2 facilitates the deposition of histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide novel insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this poor prognostic disease. RNASeq of MV4;11 cell treated with DMSO, I-BET, SGC0946 and combination of I-BET and SGC0946 in duplicate

2016-06-12 | E-GEOD-71777 | biostudies-arrayexpress

ChIPSeq of MV4;11 cell treated with SGC0946 for 8 hours and washout

2016-06-12 | E-GEOD-71779 | biostudies-arrayexpress

Antitumor effects of DOT1L inhibition in retinoblastoma

Project description:Antitumor effects of DOT1L inhibition in retinoblastoma

| PRJNA728658 | ENA

Neoantigen-specific stem cell memory-like CD4+ T cells mediate immunotherapy of solid tumors

Project description:The expansion of neoantigen (NeoAg)-specific T cells often accompanies clinical responses to immunotherapies, highlighting the importance of these cells for antitumor immunity. While NeoAg-specific CD8+ T cells have been broadly studied, the role of NeoAg-specific CD4+ T cells is less well understood. To study the antitumor mechanisms of NeoAg-specific CD4+ T cells, we sorted single CD4+ T cells specific for an epitope derived from a mutated clathrin heavy chain gene (CLTCH129>Q) expressed by the murine squamous cell carcinoma VII (SCC VII) tumor. T cell receptor (TCR) sequencing analysis revealed the presence of four distinct TCR clonotypes and expression of these TCRs in primary cells was sufficient to confer preferential recognition of CLTCH129>Q as compared to the corresponding wildtype CLTC epitope. Despite differences in TCR avidity, both moderate and high avidity CD4+ T cells were capable of proliferating to similar levels in response to tumor antigen in vivo and enhancing primary tumor immunity in a CD8+ T cell- and CD40L-dependent manner. Finally, we demonstrate that adoptive cellular therapy (ACT) with T stem cell memory (TSCM)-like CLTCH129>Q-specific CD4+ T cells differentiated ex vivo in culture with IL-7 and IL-15 promotes therapeutic tumor immunity associated with enhanced T cell persistence, maintenance of adoptively transferred TSCM-like cells in the tumor-draining lymph node (tdLN), and activation of CD8+ T cells in the tdLN. Overall, these findings illuminate the mechanistic role of NeoAg-specific CD4+ T cells in tumor immunity, provide insights into the impact of TCR avidity on the helper functions of CD4+ T cells, and highlight the therapeutic potential of ACT with TCR-engineered CD4+ T cells.

2023-05-24 | GSE229221 | GEO

Transcriptional profiling of chemical Dot1L inhibition during reprogramming to induced pluripotent stem cells

Project description:Three independent transcriptional profiling experiments were performed to ascertain how Dot1L affects cell fate change. 1) In a timecoure ("Tc"), reprogramming mouse embryonic fibroblasts were treated with DMSO control or Dot1L inhibitor (Dot1Li -SGC0946) for 2 or 4 days. Surprisingly, despite the enrichment of H3K79me2 on thousands of actively transcribed genes, Dot1L inhibition (Dot1Li) results in few changes in steady state mRNA levels during reprogramming, the majority of which are spuriously upregulated. 2) To determine if Dot1Li increased reprogramming beyond the mesenchymal to epithelial transition (MET) that occurs early in reprogramming when starting from MEFs, reprogramming cells were sorted ("Sort") for surface CDH1 expression, and then treated with Dot1Li or control. Dot1Li increased reprogramming efficiency of both CDH1- and CDH1+ populations to a similar extent and few genes were DE. 3) To assess if Dot1Li increased pluripotency acquisition beyond CDH1 upregulation, CDH1 or empty vector was expressed ("Exp") in reprogramming cells. CDH1 expression did not initiate MET, or enhance reprogramming.

2021-04-30 | GSE160580 | GEO

The role of AF10 (Mllt10) in maintaining cell identity (RNA-Seq)

Project description:AF10 is a cofactor of the H3K79 methyltransferase DOT1L. To uncover the role of H3K79me in reprogramming to induced pluripotent stem cells (iPSCs), we bred reprogrammable mice encoding doxycycline inducible Oct4-2A-Klf4-2A-IRES-Sox2-2A-c-Myc (OKSM) transgene with conditional flox (fl)-AF10 (Mllt10). We isolated mouse embryonic fibroblasts (MEFs), deleted AF10 with CRE-recombinase or treated cells with empty vector control, and initiated reprogramming in DOT1L chemical inhibitor SGC0946 or DMSO control. Gene expression was assessed using RNA-Seq and genome wide localization of H3K79me1 and H3K79me2 was determined by ChIP-Seq on day 4 of reprogramming.

2023-04-01 | GSE214139 | GEO

Apoptosis-regulated low avidity cancer-specific CD8+ T cells can be rescued to eliminate HER-2/neu expressing tumors by costimulatory agonists in tolerized mice

Project description:A major barrier of vaccines as cancer treatment is their failure to activate and maintain a complete cancer-specific CD8+ effector T cell repertoire. Low avidity T cells are more likely to escape clonal deletion in the thymus when compared to higher avidity T cells, and therefore comprise the major population of effector T cells available for activation in cancer patients. However, low avidity T cells fail to traffic into the tumor microenvironment and function in eradicating tumor under optimal vaccination conditions as opposed to higher avidity T cells that escape clonal deletion and do function in tumor killing. We utilized high and low avidity TCR transgenic CD8+ T cells specific for the immunodominant epitope of HER-2/neu (RNEU420-429) to identify signaling pathways responsible for the inferior activity of low avidity T cells. Adoptive transfer of these cells into tumor-bearing vaccinated mice identified members of apoptosis pathways as being upregulated in low avidity T cells. The increased expression of pro-apoptotic proteins by low avidity T cells promoted their own cell death and also that of other tumor-specific CD8+ T cells within their local environment. Importantly, this pro-apoptotic effect was overcome using a strong costimulatory signal that prevents activation-induced cell death and enables low avidity T cells to traffic into the tumor and assist in tumor clearance. These findings identify new therapeutic opportunities for activating the most potent anticancer T cell responses. High and low avidity T cells were isolated from TCR transgenic mice and adoptively transferred into Cy-treated, vaccinated, neu-N mice. Three days after adoptive transfer T cells were isolated from the tumor draining nodes and RNA was extracted for gene expression analysis.

2014-01-14 | E-GEOD-54020 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data