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PROVIDER: PRJNA1117212 | ENA |
REPOSITORIES: ENA
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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. We performed global CpG methylation-sequencing in a CTCL cell line and in patient cells. Results showed a subset of genes with a unique change in methylation profile in the combination treatment as compared to single drugs.
2016-03-30 | E-GEOD-66732 | biostudies-arrayexpress
Project description:Cutaneous T-cell lymphomas (CTCL) are an aggressive group of T-cell lymphomas that present in the skin and are associated with dismal prognosis. Romidepsin is a histone deacetylase (HDAC) inhibitor that is an FDA approved systemic therapeutic indicated for the treatment of CTCL in patients who have received at least one prior systemic therapy. Romidepsin demonstrates promising single agent activity in patients with advanced stages of CTCL, however response is typically low and not durable. One method of overcoming resistance to romidepsin and improving response is through combination therapies. Here, we demonstrate that romidepsin in combination with the epidermal growth factor receptor (EGFR) inhibitor afatinib and afatinib dimaleate produce strongly synergistic anti-tumor effects in CTCL cell lines and an in vivo model of CTCL. Gene expression and western blot analysis further identifies the decreased activation of the JAK-STAT signalling pathway as a key driver of synergy in this combination. These results suggest a potential indication for FDA-approved EGFR inhibitors previously unrecognized in CTCLs as a combination therapeutic with HDAC inhibitors that can be rapidly adopted in the clinic.
2024-07-12 | GSE237167 | GEO
Project description:Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing chronic inflammation, tissue destruction, severe infections and sepsis, all linked to poor quality of life and high mortality. Despite numerous sequencing efforts in L-CTCL, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analysis with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. In order to examine IQDMA-specific effects in an unbiased and dose-dependent manner without limiting the analysis to only kinases, we carried out global proteomics profiling in SeAx cells after 24 h treatment with 1, 2.5 and 10 µM IQDMA. The differential proteins affected in response to increasing IQDMA concentrations were found to be related to multiple cellular processes in metabolism, ribosomal RNA processing/modification, protein translation, and surprisingly keratinization.. Dual inhibition of STAT3/5 using small molecule degraders abolished L-CTCL cell growth in vitro. Furthermore, upstream broad range kinase targeting through IQDMA, a newly classified multi-kinase inhibitor, revealed a pharmacologic opportunity to alternatively block the STAT3/5 pathway by inhibiting the PAK2 serine/threonine kinase, which was very effective in patient cells carrying STAT3/5 copy number gains and in vivo in reducing tumor growth and disease dissemination in an intradermal xenograft mouse model. In summary, we conclude that STAT3/5 and PAK2 are new therapy targets to be further explored in L-CTCL.
2023-03-11 | PXD035626 | Pride
Project description:Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing chronic inflammation, tissue destruction, severe infections and sepsis, all linked to poor quality of life and high mortality. Despite numerous sequencing efforts in L-CTCL, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analysis with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. In order to examine IQDMA-specific effects in an unbiased and dose-dependent manner without limiting the analysis to only kinases, we carried out global proteomics profiling in SeAx cells after 24 h treatment with 1, 2.5 and 10 µM IQDMA. The differential proteins affected in response to increasing IQDMA concentrations were found to be related to multiple cellular processes in metabolism, ribosomal RNA processing/modification, protein translation, and surprisingly keratinization.. Dual inhibition of STAT3/5 using small molecule degraders abolished L-CTCL cell growth in vitro. Furthermore, upstream broad range kinase targeting through IQDMA, a newly classified multi-kinase inhibitor, revealed a pharmacologic opportunity to alternatively block the STAT3/5 pathway by inhibiting the PAK2 serine/threonine kinase, which was very effective in patient cells carrying STAT3/5 copy number gains and in vivo in reducing tumor growth and disease dissemination in an intradermal xenograft mouse model. In summary, we conclude that STAT3/5 and PAK2 are new therapy targets to be further explored in L-CTCL.
2022-10-06 | PXD035699 | Pride
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 at the induction of vorinostat and photopherisis treatment (GSE122703) and at the progression on therapy. We identifed thea decrease conventional SS cell markers on therapy and an increase in the number of cells expressing FOXP3+.
2019-06-25 | GSE124898 | GEO
Project description:Developing targeted therapy for cutaneous T cell lymphoma (CTCL) patients still requires actionable mutated genes and deregulated pathways to be identified. There is increasing evidence that activating mutations in JAK genes and deregulated JAK/STAT signaling are important mechanisms involved in multiple B and T cell malignancies, including CTCL. Therefore, in this study we focused on studying the mutational status of JAK1, JAK2 and JAK3 genes in a series of human CTCL lesions and cell lines using next-generation sequencing (NGS). We found that 7 of 48 (14.7%) of the analyzed cases harbored mutations in the JAK1 and JAK3 genes that mainly affected the pseudokinase domain of the corresponding proteins. On the basis of these results, we used a specific JAK inhibitor (INCB018424) in a series of CTCL cell lines with deregulated JAK/STAT activity. Treatment of CTCL cells with INCB018424 resulted in dose-dependent reduction of activated STAT expression, diminished cell viability, and increased apoptosis. We also studied global changes in gene expression in cells with mutated JAK1 and JAK3 proteins treated with INCB018424 and identified multiple genes that were differentially regulated by JAK/STAT signaling, such as FGF20 (upregulated) and EGR1 (downregulated). Thus, our results show that the detection of deregulated JAK/STAT signaling in CTCL lesions via JAK mutations or other surrogate markers may serve to indicate the clinical use of JAK/STAT inhibitors. 3 replicates of cells treated with DMSO or JAKi during 30 min and 3h
2015-10-31 | E-GEOD-68562 | biostudies-arrayexpress
Project description:Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by Assay of Transposase-Accessible Chromatin (ATAC-seq). Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic vs. non-leukemic (host) CD4+ T cells in CTCL patients, vs. CD4+ T cells in healthy donors. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4+ T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy.
2017-04-20 | GSE85853 | GEO
Project description:Purpose: The heterogeneity of tumor cells presents a major challenge to cancer diagnosis and therapy. Cutaneous T cell lymphomas (CTCL) are a group of T lymphocyte malignanciesthat primarily affect skin. Lack of highly specific markers for malignant lymphocytes prevents early diagnosis, while only limited treatment options are available for patients with advanced-stage CTCL.Droplet-basedsingle-cell transcriptome analysis of CTCL skin biopsiesopens avenues for dissecting patient-specificT lymphocyte heterogeneity, providing a basis for identifying specific markers for diagnosis and cure of CTCL. Experimental Design: Single-cell RNA-sequencing was performed by Droplet-based sequencing (10X Genomics), focusing on 14,056 CD3+lymphocytes (448 cells from normal and 13,608 cells from CTCL skin samples) from skin biopsies of 5 patients with advanced-stage CTCL and 4 healthy donors.Protein expression of identified genes was validated in advanced-stage CTCL skin tumors byimmunohistochemistry and confocal immunofluorescence microscopy. Results: Our analysis revealed a large inter- and intra-tumor gene expression heterogeneity in the T lymphocyte subset, as well as a common gene expression signature in highly proliferating lymphocytes that was validated in multiple advanced-stage skin tumors. In addition, we established the immunological state of reactive lymphocytes and found heterogeneity in effector and exhaution programs across patient samples. Conclusions: Single-cell analysis of CTCL skin tumor samples reveals patient-specific landscapes of malignant and reactive lymphocytes within the local microenvironment of each tumor, giving anunprecedented view of lymphocyte heterogeneity and identifying tumor-specific molecular signatures, withimportant implications for diagnosis and personalized disease treatment.
2019-05-10 | GSE128531 | 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