Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Multimodal single cell analysis of molecular profiles of paired tissues of cutaneous T cell lymphoma

ABSTRACT: Cutaneous T cell lymphoma (CTCL) is a heterogeneous group of mature T cell neoplasms characterized by the accumulation of clonal malignant CD4+ T cells in the skin. The most common variant of CTCL, Mycosis Fungoides, is confined to the skin in early stages but can be accompanied by extracutaneous dissemination of malignant T cells to the blood and lymph nodes in advanced stages of disease. Sézary Syndrome, a leukemic form of disease is characterized by significant blood involvement. Little is known about the transcriptional and genomic relationship between skin and blood residing malignant T cells in CTCL. In the present study we interrogate multiple modalities of information in single cells from matched skin and blood samples of patients with leukemic disease and healthy controls within a single workflow. By employing expanded CRISPR-compatible cellular indexing of transcriptomes and epitopes by sequencing (ECCITE-seq), we sought to compare the molecular profile of malignant clones residing in the skin and circulation of these patients across gene and protein expression modalities. We apply inferred CNV and phylogenetic analysis to examine sub-clonal heterogeneity to gain insights into the evolution and the relationship of malignant clones across tissues. Our data reveals clonal evolution at a transcriptional and genetic level within the malignant populations of individual patients. We highlight highly consistent transcriptional signatures delineating skin-derived and blood-derived malignant T cells. Analysis of these two populations suggests that environmental cues, along with genetic aberrations, contribute to transcriptional profiles of malignant T cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171811 | GEO | 2021/07/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Comprehensive transcriptional and clonotypic analysis of peripheral blood constituents in Sézary syndrome.

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

Single-cell profiling of cutaneous T-cell lymphoma reveals underlying heterogeneity predicting with disease progression.

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

PBMCs from healthy donors and CTCL patient control vs SEB stimulation

Project description:Transcriptional profiling of peripheral blood mononuclear cells from healthy donors and leukemic CTCL patients upon recombinant SEB treament.

2022-09-01 | GSE182452 | GEO

Identification of p38 beta as a therapeutic target for the treatment of Sézary Syndrome

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

Transcription profiling of human skin biopsies in cutaneous T-cell lymphoma

Project description:Cutaneous T cell lymphoma (CTCL) is defined by infiltration of activated and malignant T cells in skin. The clinical manifestations and prognosis in CTCL are highly variable. In this study, we hypothesized that gene expression analysis in lesional skin biopsies can improve understanding of the disease and its management. Based on 63 skin samples, we performed consensus clustering, revealing three patient clusters. Two clusters tended to differentiate limited CTCL (stages IA and IB) from more extensive CTCL (stages IB and III). Stage IB subjects appeared in both clusters, but those in the limited CTCL cluster were more responsive to treatment than those in the more extensive CTCL cluster. The third cluster was enriched in lymphocyte activation genes and was associated with a high proportion of tumor (stage IIB) lesions. Survival analysis revealed significant differences in event-free survival between clusters, with poorest survival seen in the activated lymphocyte cluster. Using supervised analysis, we further characterized genes significantly associated with lower stage/treatment responsive versus higher stage/treatment resistant CTCL. We conclude that transcriptional profiling of CTCL skin lesions reveals clinically relevant signatures, correlating with differences in survival and response to treatment. Additional prospective long-term studies to validate and refine these findings appear warranted. Experiment Overall Design: 63 skin biopsies from patients with different stages of disease were selected for RNA extraction and hybridization on Affymetrix microarrays

2008-06-16 | E-GEOD-9479 | biostudies-arrayexpress

caArray_kuppe-00390: Broad: Lesional gene expression profiling in cutaneous T-cell lymphoma reveals natural clusters associated with disease outcome

Project description:Cutaneous T-cell lymphoma (CTCL) is defined by infiltration of activated and malignant T cells in the skin. The clinical manifestations and prognosis in CTCL are highly variable. In this study, we hypothesized that gene expression analysis in lesional skin biopsies can improve understanding of the disease and its management. Based on 63 skin samples, we performed consensus clustering, revealing 3 patient clusters. Of these, 2 clusters tended to differentiate limited CTCL (stages IA and IB) from more extensive CTCL (stages IB and III). Stage IB patients appeared in both clusters, but those in the limited CTCL cluster were more responsive to treatment than those in the more extensive CTCL cluster. The third cluster was enriched in lymphocyte activation genes and was associated with a high proportion of tumor (stage IIB) lesions. Survival analysis revealed significant differences in event-free survival between clusters, with poorest survival seen in the activated lymphocyte cluster. Using supervised analysis, we further characterized genes significantly associated with lower-stage/treatment-responsive CTCL versus higher-stage/treatment-resistant CTCL. We conclude that transcriptional profiling of CTCL skin lesions reveals clinically relevant signatures, correlating with differences in survival and response to treatment. Additional prospective long-term studies to validate and refine these findings appear warranted. kuppe-00390 Assay Type: Gene Expression Provider: Affymetrix Array Designs: U133AAofAv2 Organism: Homo sapiens (ncbitax) Tissue Sites: Skin Material Types: total RNA, synthetic_RNA, organism_part, whole_organism Disease States: Cutaneous T-cell lymphoma

2015-06-27 | E-GEOD-70328 | biostudies-arrayexpress

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

caArray_kuppe-00390: Broad: Lesional gene expression profiling in cutaneous T-cell lymphoma reveals natural clusters associated with disease outcome

2015-06-27 | GSE70328 | GEO

The Mutational Landscape of CTCL and Sezary Syndrome.

Project description:Sezary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4+ T cells. To identify new genetic alterations involved in Sezary syndrome and CTCL transformation we performed whole-exome sequencing of tumor-normal sample pairs from 26 Sezary syndrome and 16 CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sezary syndrome including highly prevalent recurrent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A, and CDKN1B tumor suppressor genes. Mutation analysis identified a broad spectrum of somatic mutations involving key genes involved in epigenetic regulation (TET2, CREBBP, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including mutations in MAPK1, BRAF, CARD11 and PRKG1 driving increased MAPK, NFKB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sezary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.

| phs000994 | dbGaP

Comparison of pre-leukemic and leukemic H9M AML clones from murine splenocytes

Project description:The tracking of leukemic clones in acute myeloid leukemic promisses deeper insights into disease development and therapeutic options. We therefore established a fluorescent genetic barcoding (FGB) labeling approach that allows for flow cytomtric tracking of color-coded clones in vitro and in vivo. In Hoxa9 and Meis1 (H9M) dependent murine AML, we tracked the growth behavior of 24 clones in parallel and enriched for pre-leukemic clones as well as their de novo expanded counterparts and stably expanded clones from leukemic mice by fluorescence-activated cell sorting. These samples were subjected toRNA sequencing for the assessment of transcriptional changes underlying clonal maintenance and expansion.

2022-12-28 | GSE198371 | GEO

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