Single-cell profiling of cutaneous T-cell lymphoma after treatment with vorinostat and photophoresis.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE124898 | GEO | 2019/06/25
REPOSITORIES: GEO
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Project description:Cutaneous T cell lymphomas (CTCL), encompassing a spectrum of T-cell lymphoproliferative disorders involving the skin, have collectively increased in incidence over the last 40 years. Sézary syndrome (SS) is an aggressive form of CTCL characterized by significant presence of malignant cells in both the blood and skin. The guarded prognosis for SS reflects a lack of reliably effective therapy, due in part to an incomplete understanding of disease pathogenesis. Using single-cell sequencing of RNA, we confirm that SS is a clonal disease, but we further define a more complex model featuring distinct transcriptomic states within SS. Our analysis showed the involvement of FOXP3+ malignant T cells during clonal evolution, transitioning from FOXP3+ T cells to GATA3+ or IKZF2+ (HELIOS) tumor cells. Transcriptomic diversities in a clonal tumor can be used to predict disease stage, and we were able to characterize a gene signature that predicts disease stage with close to 80% accuracy. Supporting the critical role of FOXP3+ T cell involvement during clonal evolution, FOXP3 was found to be the most important factor to predict early disease in SS, along with another 19 genes used to predict CTCL stage. This work offers insight into the heterogeneity of SS, providing better understanding of the transcriptomic diversities within a clonal tumor, which can predict tumor stage and thereby offer guidance of therapy.
2019-03-22 | GSE122703 | GEO
Project description:Cutaneous T-Cell Lymphomas (CTCL) represent a group of hematopoietic malignancies that home to the skin and have no known molecular basis for disease pathogenesis. Sézary syndrome (SS) is the leukemic variant of CTCL. Currently, CTCL is incurable, highlighting the need for new therapeutic modalities. We have previously observed that combined small-molecule inhibition of protein kinase C (PKC) β and glycogen synthase kinase 3 (GSK3) causes synergistic apoptosis in CTCL cell lines and patient cells. Through microarray analysis of a SS cell line, we surveyed global gene expression following combined PKCβ-GSK3 treatment to elucidate therapeutic targets responsible for cell death. Clinically relevant targets were defined as genes differentially expressed in SS patients that were modulated by combination-drug treatment of SS cells. Gene set enrichment analysis uncovered candidate genes enriched for an immune cell signature, specifically the T-cell receptor and MAPK signaling pathways. Further analysis identified p38 as a potential therapeutic target that is over-expressed in SS patients and decreased by synergistic-inhibitor treatment. This target was verified through small-molecule inhibition of p38 leading to cell death in both SS cell lines and patient cells. These data establish p38 as a new SS biomarker and potential therapeutic target for the treatment of CTCL. Hut78 cells were treated with 4μM Enzastaurin, 5μM AR-A014418, 4μM Enzastaurin & 5μM AR-A014418, DMSO, or no treatment for three days. RNA was extracted and hybridized to Illumina microarrays.
2015-07-01 | E-GEOD-59179 | biostudies-arrayexpress
Project description:Suberoyl Anilide Hydroxamic Acid (SAHA), also named under Vorinostat, is an inhibitor of class I and II histone deacetylases (HDACi) approved by the USA Food and Drug Administration (FDA) for the treatment of advanced and refractory cutaneous T-cell lymphomas (CTCL). Its limited efficacy led to its use in various combination therapies. Given that SAHA modifies the expression of many genes under control of Sp1 (or Sp3) transcription factors, we investigated here its association to the FDA-approved anticancer antibiotic Mithramycin (MitA), a direct inhibitor of the binding of Sp1 family factors to GC-rich DNA promoters. We found that MitA alone, similar to SAHA, efficiently induced the apoptotic death of peripheral blood lymphocytes from Sézary syndrome (SS) patients while the two drugs in combination demonstrated a synergistic effect that could even overcome the resistance to MitA used in mono-treatment. A deep analysis of gene expression profiling suggested that SAHA and MitA, either independently or synergistically, counteracted many intertwined pro-survival pathways mis-regulated in SS cells as TCR, Notch1, mTOR, PI3K/Akt, JAK/STAT and b-catenin pathways, as well as the resistance of these tumors to intrinsic and extrinsic apoptosis. This analysis also suggested that SAHA/MitA combined treatment might efficiently oppose to the abnormal adhesion, migration and invasive properties of SS cells, in addition their immunosuppressive behavior. Finally, from a mechanistic point of view, our observations strongly support a major role of additive or synergistic epigenetic modifications in the combined effect of the two drugs, with a rather limited contribution of Sp1 (or Sp3)-mediated transcriptional regulation. Peripheral blood tumor cells from Sézary patients were expanded in vitro and treated with SAHA and/or MitA previous to RNA isolation and Microarray processing. Deep analysis of gene expression profiling suggested that SAHA and Mithramycin A (MitA), either independently or synergistically, counteracted many interwined pro-survival pathways mis-regulated in Sézary cells, as well as abnormal adhesion, invasion and invasive properties. Data also favored additive or synergistic epigenetic modifications in the combined effect of the two drugs.
2016-12-12 | GSE64119 | GEO
Project description:Cutaneous T-Cell Lymphomas (CTCL) represent a group of hematopoietic malignancies that home to the skin and have no known molecular basis for disease pathogenesis. Sézary syndrome (SS) is the leukemic variant of CTCL. Currently, CTCL is incurable, highlighting the need for new therapeutic modalities. We have previously observed that combined small-molecule inhibition of protein kinase C (PKC) β and glycogen synthase kinase 3 (GSK3) causes synergistic apoptosis in CTCL cell lines and patient cells. Through microarray analysis of a SS cell line, we surveyed global gene expression following combined PKCβ-GSK3 treatment to elucidate therapeutic targets responsible for cell death. Clinically relevant targets were defined as genes differentially expressed in SS patients that were modulated by combination-drug treatment of SS cells. Gene set enrichment analysis uncovered candidate genes enriched for an immune cell signature, specifically the T-cell receptor and MAPK signaling pathways. Further analysis identified p38 as a potential therapeutic target that is over-expressed in SS patients and decreased by synergistic-inhibitor treatment. This target was verified through small-molecule inhibition of p38 leading to cell death in both SS cell lines and patient cells. These data establish p38 as a new SS biomarker and potential therapeutic target for the treatment of CTCL.
2015-07-01 | GSE59179 | GEO
Project description:Although central to the diagnosis of cutaneous T cell lymphoma (CTCL) is the malignant clonal proliferation of skin-tropic T cells the diagnosis represents a spectrum of diseases and clinical courses. Most patients have an indolent disease course with cycling of therapies, while others, especially in advanced stages of disease, have aggressive progression and poor median survival. Adding to the difficulty of treatment, Sézary syndrome (SS), a leukemic variant of CTCL, lacks highly characteristic phenotypic and genetic markers that would aid in not only the diagnosis of the malignancy, but also response to therapies. Using single-cell mRNA and T-cell-receptor sequencing, of peripheral blood immune cells in SS, we extensively mapped the transcriptomic variations of nearly 50,000 T cells of both malignant and nonmalignant origins. We identified potential diverging SS cell populations, including quiescent and proliferative populations shared across multiple patients.
2022-03-04 | GSE146586 | GEO
Project description:We demonstrate that the combination of the HDAC inhibitor, romidepsin, and the demethylating agent, azacitidine, exerts synergistic anti-proliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL cell lines as well as CD4+ T cells derived from patients with Sézary Syndrome (SS) with high tumor burden. We identified genes that were selectively induced by the combination treatment, such the tumor suppressor gene RhoB.
2016-03-30 | GSE66732 | GEO
Project description:Cutaneous T-cell lymphomas are a heterogeneous group of neoplasms originating in the skin, with mycosis fungoides (MF) and Sézary syndrome (SS) representing the most common variants. The cellular origin of cutaneous lymphomas has remained controversial due to their immense phenotypic heterogeneity that obfuscates lineage reconstruction based on classical surface biomarkers. To overcome this heterogeneity and reconstruct the differentiation trajectory of malignant cells in MF and SS, T-cell receptor sequencing was performed in parallel with targeted transcriptomics at the single-cell resolution among cutaneous samples in MF and SS. Unsupervised lineage reconstruction showed that Sézary cells exist as a population of CD4+ T cells distinct from those in patch, plaque, and tumor MF. Further investigation of malignant cell heterogeneity in SS showed that Sézary cells phenotypically comprised at least three subsets based on differential proliferation potentials and expression of exhaustion markers. A Th1 polarized cell type, intermediate cell type, and exhausted Th2 polarized cell type were identified, with Th1 and Th2 polarized cells displaying divergent proliferation potentials. Collectively, these findings provide evidence to clarify the relationship between MF and SS, and reveal cell subsets in SS that suggest a possible mechanism for therapeutic resistance.
2022-12-31 | GSE192836 | GEO
Project description:Acute myeloid leukaemia (AML) is a highly heterogeneous entity of disorders in haematopoietic progenitors, characterised by an arrest in differentiation and an outgrowth of myeloid blasts in the bone marrow. AML is a disease of the aging, many patients are unable to withstand standard chemotherapy therefore novel approaches for anti-cancer agents has arisen in the understanding of epigenetic regulation in cancer cells, such as chromatin remodelling. Acetylation of histones is a reversible process, whereby acetyl groups are transferred on the ε-amino groups of specific lysine residues by a specific group of enzymes, histone acetyltransferases (HATs) and removed by histone deacetylase complexes (HDACs). HDACs are involved in regulating a number of processes in the cell, such as cell proliferation, differentiation as well as apoptosis. Deregulation of the activity of these enzymes is associated with cancer; therefore it is important that the HAT and HDAC equilibrium is regained. This equilibrium can be improved through the inhibition of HDAC enzymes using HDAC inhibitors. Vorinostat is a HDAC inhibitor, clinically approved for the treatment of CTCL, and is in phase II clinical trials for AML and a number of haematological malignancies. Studies have shown that some patients are non-responsive/resistant to Vorinostat; therefore a fuller characterisation of Vorinostat needs to be made so an adequate combination drug can be identified, as understanding of resistance is crucial to overcoming it. The purpose of this study was to provide a comprehensive analysis of Vorinostat in AML cell lines and to identify potential synergistic therapies that could be used in combination with Vorinostat to provide a better outlook in AML. The global identification of genes associated with Vorinostat induced histone H3 lysine 9 (H3K9) acetylation, investigated using chromatin immunoprecipitation coupled with next generation sequencing (ChIP-SEQ), was integrated with data from gene expression studies to provide a comprehensive approach to understanding Vorinostat. This study has identified the sonic hedgehog homolog (SHH) as a rational and potential therapeutic target for combination therapy with Vorinostat
2017-03-01 | GSE86445 | GEO
Project description:This SuperSeries is composed of the following subset Series:; GSE17595: Affymetrix SNP array data for Sézary Syndrome (SS) samples; GSE17601: Affymetrix Gene Expression array data for Sézary Syndrome (SS) samples Experiment Overall Design: Refer to individual Series
2009-10-10 | E-GEOD-17602 | biostudies-arrayexpress
Project description:Potential vorinostat-resistance candidate genes were identified using RNA interference screening in vorinostat-resistant HCT116 cells (HCT116-VR) using a synthetic lethal approach. In order to understand the mechanisms by which these genes contributed to vorinostat response, transcriptomic analysis was conducted on HCT116-VR cells and those with siRNA-mediated knockdown of each of the vorinostat resistance candidate genes.
2014-07-07 | GSE56788 | GEO