CaArray_kuppe-00390: Broad: Lesional gene expression profiling in cutaneous T-cell lymphoma reveals natural clusters associated with disease outcome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE70328 | GEO | 2015/06/27
SECONDARY ACCESSION(S): PRJNA288320
REPOSITORIES: GEO
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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
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
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. Keywords: disease state analysis
2007-11-01 | GSE9479 | 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:It is unknown why cutaneous T cell lymphoma (CTCL) progress from a relative indolent skin condition to severe cancer with a poor prognosis. Staphylococcus aureus (SA) has been suspected to play a role, because antibiotics have an inhibitory effect on the tumor burden in some patients. As these patients often display skin colonization by SA, it was hypothesized, but never proven, that SA generate a pro-oncogenic milieu in lesional skin. Here, we study the effect of short-term aggressive antibiotic treatment on tumor cells, the microenvironment, and disease activity in treatment-refractory, advanced stage CTCL. We report that advanced stage CTCL patients experienced significant decrease in clinical and patient-self-reported symptoms in response to aggressive 4-week antibiotic therapy, which eradicated SA. Notably, the clinical improvement lasted for more than 8 months in some patients. Global mRNA expression and cell-signaling pathway analysis indicated a decrease in IL-2 signaling, inflammation, and mitosis in skin lesions after antibiotic therapy. In accordance, IL-2 receptor chain (IL2R-) expression, STAT3 activation, and mitotic activity were decreased in lesional skin following antibiotic treatment. Conversely, SA toxins triggered IL2R- expression, STAT3 activation, and enhanced proliferation ex vivo in primary malignant T cells derived from untreated patients. In conclusion, we demonstrate that transient, aggressive antibiotic treatment inhibits tumor cells, partly normalizes the microenvironment, and decreases disease activity in lesional skin. Thus, we provide a first mechanistic link between antibiotics, skin inflammation, and tumor burden and therefore a novel rationale for treatment of SA in advanced CTCL.
2020-04-13 | GSE122934 | GEO
Project description:Background: Malignant clones of primary cutaneous T-cell lymphomas (CTCL) can show a CD4+, CD8+ or T-cell receptor γδ+ phenotype, but their individual impact on tumor biology and skin lesion formation remains ill-defined. We perform a comprehensive molecular characterization of CD4+ vs. CD8+ and TCR-γ/δ+ CTCL lesions. Methods: We performed scRNA-seq of 18 CTCL skin biopsies to compare classic CD4+ advanced-stage mycosis fungoides (MF) with TCR-γ/δ+ MF and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (Berti’s lymphoma). Results: Malignant clones of TCR-γ/δ+ MF and Berti’s lymphoma showed similar clustering patterns distinct from CD4+ MF, along with increased expression of cytotoxic markers such as NKG7, CTSW, GZMA, and GZMM. Only advanced-stage CD4+MF clones expressed central memory T-cell markers (SELL, CCR7, LEF1), alongside B1/B2 blood involvement, whereas TCR-γ/δ+ MF and Berti’s lymphoma harbored a more tissue-resident phenotype (CD69, CXCR4, NR4A1) without detectable cells in the blood. CD4+ MF and TCR-γ/δ+ MF skin lesions harbored strong type 2 immune activation across myeloid cells, while Berti’s lymphoma was more skewed towards type 1 immune responses. Both CD4+ MF and TCR-γ/δ+ MF lesions showed upregulation of keratinocyte hyperactivation markers such as S100As and KRT16 genes. This increase was entirely absent in Berti’s lymphoma, possibly reflecting an aberrant keratinocyte response to invading tumor cells, that could contribute to the formation of the typical ulcero-necrotic lesions within this entity. Conclusions: Our scRNAseq profiling study reveals specific molecular patterns associated with distinct CTCL subtypes.
2024-10-24 | GSE266862 | GEO
Project description:Cutaneous T-cell lymphoma (CTCL) develops from clonally expanded CD4+ T cells in a background of chronic inflammation. Dendritic cells (DCs) are potent T-cell stimulators; yet despite DCs’ extensive presence in skin, cutaneous T cells in CTCL do not respond with effective anti-tumor immunity. We evaluated primary T-cell and DC émigrés from epidermal and dermal explant cultures of skin biopsies from CTCL patients (n = 37) and healthy donors (n = 5). Compared with healthy skin, CD4+ CTCL populations contained more T cells expressing PD-1, CTLA-4, and LAG-3; and CD8+ CTCL populations comprised more T cells expressing CTLA-4 and LAG-3. CTCL populations also contained more T cells expressing the inducible T-cell costimulator (ICOS), a marker of T-cell activation. DC émigrés from healthy or CTCL skin biopsies expressed PD-L1, indicating that maturation during migration resulted in PD-L1 expression irrespective of disease. Most T cells did not express PD-L1. Using skin samples from 49 additional CTCL patients for an unsupervised analysis of genome-wide mRNA expression profiles corroborated that advanced T3/T4 stage samples expressed higher levels of checkpoint inhibition genes compared with T1/T2 stage patients or healthy controls. Exhaustion of activated T cells is therefore a hallmark of both CD4+ and CD8+ T cells directly isolated from the lesional skin of patients with CTCL, with a continuum of increasing expression in more advanced stages of disease. These results justify identification of antigens driving T-cell exhaustion and the evaluation of immune checkpoint inhibition to reverse T-cell exhaustion earlier in the treatment of CTCL.
2018-08-21 | GSE113113 | GEO
Project description:Cutaneous T-cell lymphomas (CTCL) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult due to a clinical and histological resemblance to benign inflammatory skin diseases. To address if microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we study miRNA expression in 199 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays we show that the most induced- (miR-326, miR-663b, miR-711) and repressed- (miR-203, miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Q-RT-PCR analysis of 104 patients with CTCL and benign skin disorders validates differential expression of 4 out of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A q-RT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity, sensitivity, and a classification accuracy of 95% indicating that miRNAs have a high diagnostic potential in CTCL.
2011-11-22 | GSE31408 | GEO
Project description:Cutaneous T-cell lymphomas (CTCL) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult due to a clinical and histological resemblance to benign inflammatory skin diseases. To address if microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we study miRNA expression in 199 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays we show that the most induced- (miR-326, miR-663b, miR-711) and repressed- (miR-203, miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Q-RT-PCR analysis of 104 patients with CTCL and benign skin disorders validates differential expression of 4 out of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A q-RT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity, sensitivity, and a classification accuracy of 95% indicating that miRNAs have a high diagnostic potential in CTCL. miRNA microarray. From each sample 100 ng of total RNA was labeled with Hy3 fluorescent dye using the miRCURY LNA Array power labeling kit (Exiqon, Denmark). All samples were labeled the same day with the same master mix, in order to minimize technical variation. The Hy3-labelled samples were hybridized to miRCURY LNA arrays (v11.0) (Exiqon, Denmark), containing capture probes targeting all human miRNAs registered in the miRBASE version 15.0 at the Sanger Institute. The hybridization was performed overnight at 56°C according to manufacturer specifications using a Tecan HS4800 hybridization station (Tecan, Austria). Since it was not possible to hybridize all arrays in one go, samples were randomly split into 5 batches as to minimize day to day variation in the hybridization process. After hybridization the microarray slides were scanned using an Agilent G2565BA Microarray Scanner System (Agilent Technologies, Inc., USA) at 5µm resolution, and the resulting TIFF images were analyzed using the ImaGene 8.0 software on standard settings (BioDiscovery, Inc., USA).
2011-11-22 | E-GEOD-31408 | biostudies-arrayexpress
Project description:Infants diagnosed of precursor B-cell acute lymphoblastic leukemia (iB-ALL) presenting MLL-AF4 chromosomal rearrangement are at high risk of disease progression into fatal outcome. This specific subtype of pediatric leukemia constitutes a tough challenge in leukemia research, given the difficulties found when trying in vivo modelling. However, the understanding of mechanisms leading to proper lymphocyte generation may become of high utility in gaining deep insight on this malignancy. As we report here, the lack of HDAC7, a key transcriptional regulator in B lymphocyte differentiation, worsens the prognosis of iB-ALL patients. In fact, MLL-AF4+ iB-ALL patients with high expression of HDAC7 display an improved survival, partially mediated by the repression of oncogenes, such as c-MYC, and chemoresistance markers, like the ASNS enzyme. Accordingly, HDAC7 drastically reduces leukemic cells proliferation in MLL-AF4+ iB-ALL through the induction of apoptosis. Moreover, RNA sequencing of HDAC7-overexpressing cells has revealed that HDAC7 alters the genomic profiling of MLL-AF4+ iB-ALL cells towards that of healthy B-cell progenitors. In summary, the findings here reported highlight the role of HDAC7 in predicting prognosis of a lethal subtype of iB-ALL and open new clinical perspectives, since MLL-AF4+ iB-ALL infants would highly benefit from therapeutic options eventually restoring HDAC7 expression.
2021-06-04 | GSE151793 | GEO