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Tumor RNA sequencing identifies a group of Mycosis Fungoides patients with failure of skin-directed therapies

ABSTRACT: Mycosis fungoides (MF), the most common type of primary cutaneous T-cell lymphoma, has a heterogeneous clinical course, and the factors determining disease progression from the indolent to the aggressive disease stages are not well known. Our previous study described prognostic groups of MF cases according to the transcription factors Twist and Zeb1. Using Twist expression, we differentiated distinct groups based on their global RNA expression. Using the same dataset with 40 formalin-fixed paraffin-embedded MF samples, we performed RNA sequencing using bioinformatics tools. Based on the consensus clustering, we defined four clusters with different disease pathologies and prognostic groups. Cluster 3 showed the shortest time to skin-directed therapy failure (p=0.031), and with Cluster 1 they included all the MF-related deaths (2/40). Cluster 3 presented a higher proportion of lymphocytic infiltrates per sample (p<0.001), with the highest percentages (>60 %) and a higher rate of CD30+ tumor cells (over 10 %, p=0.048). Cluster 3 samples also showed upregulated genes related to keratinocyte, basal cell, and melanocyte activities. This is the first study to describe the association between gene expression, tumor cell density, reactive cell infiltration, and failure of skin-directed therapies

ORGANISM(S): Homo sapiens

PROVIDER: GSE272226 | GEO | 2024/07/18

REPOSITORIES: GEO

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Genetics of Cutaneous T-Cell Lymphoma

Project description:<p>Mycosis fungoides (MF) is a common extranodal T-cell lymphoma primarily arising in the skin. In early disease stages, MF presents as skin patches and plaques that in some cases may progress to tumor and disperse to lymph nodes and other internal organs. The 10-year overall survival is 50% in advanced stages. Early diagnosis is difficult as the histology overlaps with features of inflammatory skin diseases. Even when the diagnosis is established, there are no prognostic markers that predict whether the disease will be aggressive or indolent. Lastly, there are no curative treatments and MF will invariably relapse, even after aggressive chemotherapy. The disease is a diagnostic, prognostic and therapeutic challenge. The main objective of this study is to address the question of tumor heterogeneity in MF. To date, MF is considered to be monoclonal, derived from a transformed, mature memory T-cell. However, clinical observations and preliminary data suggest that MF comprises multiple subclones, which may be of importance for understanding disease evolution and resistance to therapy. We plan to address this objective using Whole Exome Sequencing (WES) of MF tissue prepared by laser microdissection (LMD).</p>

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Transcription profiling of human cutaneous B-cell lymphoma skin punch biopsies, mycosis fungoides (MF) and 3 normal skin biopsies

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Identification of gene expression signatures for phenotype-specific drug targeting of cardiac remodeling

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Project description:Background: In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Nevertheless, approximately 20-30% of cases progress to tumors or erythroderma, resulting in poor outcome. At present, factors contributing to this switch from indolent to aggressive disease are only insufficiently understood. Methods: In patients with advanced-stage MF, we compared patches with longstanding history to newly developed plaques and tumors by using single-cell RNA sequencing, and compared results with early-stage MF as well as nonlesional MF and healthy control skin. Results: Despite considerable inter-individual variability, lesion progression was uniformly associated with downregulation of the tissue residency markers CXCR4 and CD69, the heat shock protein HSPA1A, the tumor suppressors and immunoregulatory mediators ZFP36 and TXNIP, and the interleukin 7 receptor (IL7R) within the malignant clone, but not in benign T cells. This phenomenon was not only found in conventional TCR-αβ MF, but also in a case of TCR-γδ MF, suggesting a common mechanism across MF subtypes. Conversely, malignant cells in clinically unaffected skin from MF patients showed upregulation of these markers. Conclusions: Our data reveal a specific panel of biomarkers that might be used for monitoring MF disease progression. Altered expression of these genes may underlie the switch in clinical phenotype observed in advanced-stage MF.

2021-09-13 | GSE173205 | GEO

Single-cell RNA sequencing comparison of CD4+, CD8+ and T-cell receptor γδ+ cutaneous T-cell lymphomas reveals subset-specific molecular phenotypes

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

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Project description:SCOPE: We investigated whether a novel dietary intervention consisting of an every-other-week calorie-restricted diet could prevent nonalcoholic fatty liver disease (NAFLD) development induced by a medium-fat (MF) diet. METHODS AND RESULTS: Nine-week-old male C57BL/6J mice received either a (i) control (C), (ii) 30E% calorie restricted (CR), (iii) MF (25E% fat), or (iv) intermittent (INT) diet, a diet alternating weekly between 40E% CR and an ad libitum MF diet until sacrifice at the age of 12 months. The metabolic, morphological, and molecular features of NAFLD were examined. The INT diet resulted in healthy metabolic and morphological features as displayed by the continuous CR diet: glucose tolerant, low hepatic triglyceride content, low plasma alanine aminotransferase. In contrast, the C- and MF-exposed mice with high body weight developed signs of NAFLD. However, the gene expression profiles of INT-exposed mice differed to those of CR-exposed mice and showed to be more similar with those of C- and MF-exposed mice with a comparable body weight. CONCLUSIONS: Our study reveals that the INT diet maintains metabolic health and reverses the adverse effects of the MF diet, thus effectively prevents the development of NAFLD in 12-month-old male C57BL/6J mice. Male C57Bl/6J mice were divided to 4 dietary intervention groups: Control (AIN-93W), 30% calorie restriction (CR; AIN-93W-CR), medium fat (MF; AIN-93W-MF; 25% energy from fat) and intermittent diet (INT; weekly alternating diet between AIN-93W-MF ad lib and 40% CR of AIN-93W). We performed various measurements on metabolic parameters and gene expression analysis on the liver. This entry represents the microarray data of the liver gene expression of each mouse.

2015-10-26 | E-GEOD-61233 | biostudies-arrayexpress

Single-cell RNA sequencing reveals tissue compartment-specific plasticity of mycosis fungoides tumor cells

Project description:Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. While initially restricted to the skin, malignant cells can appear in blood, bone marrow and secondary lymphoid organs in later disease stages. However, only little is known about phenotypic and functional properties of malignant T cells in relationship to tissue environments over the course of disease progression. We thus profiled the tumor micromilieu in skin, blood and lymph node in a patient with advanced MF using single-cell RNA sequencing combined with V-D-J T-cell receptor sequencing. In skin, we identified clonally expanded T-cells with characteristic features of tissue-resident memory T-cells (TRM, CD69+CD27-NR4A1+RGS1+AHR+). In blood and lymph node, the malignant clones displayed a transcriptional program reminiscent of a more central memory-like phenotype (KLF2+TCF7+S1PR1+SELL+CCR7+), while retaining tissuehoming receptors (CLA, CCR10). The skin tumor microenvironment contained potentially tumor-permissive myeloid cells producing regulatory (IDO1) and Th2-associated mediators (CCL13, CCL17, CCL22). Given their expression of PVR, TNFRSF14 and CD80/CD86, they might be under direct control by TIGIT+CTLA4+CSF2+TNFSF14+ tumor cells. In sum, this study highlights the adaptive phenotypic and functional plasticity of MF tumor cell clones. Thus, the TRM-like phenotype enables long-term skin residence of MF cells. Their switch to a TCM-like phenotype with persistent skin homing molecule expression in the circulation might explain the multi-focal nature of MF.

2021-04-13 | GSE165623 | GEO

Uncovering potential lncRNAs and mRNAs in progression from acute myocardial infarction to myocardial fibrosis to heart failure

Project description:Background: In spite of modern reperfusion therapies, morbidity and mortality of heart failure (HF) post myocardial infarction (MI) remain elevated. The aim of this study was to identify potential long non-coding RNAs (lncRNAs) and mRNAs in progression from acute myocardial infarction (AMI) to myocardial fibrosis (MF) to HF. Methods: Firstly, blood samples from 3 AMI patients, 3 MF patients and 3 HF patients were used for RNA sequencing. Secondly, differentially expressed lncRNAs and mRNAs were obtained in MF vs AMI and HF vs MF, followed by functional annotation of common differentially expressed mRNAs between two groups. Thirdly, interaction networks of lncRNA-nearby targeted mRNA and lncRNA-co-expressed mRNA were constructed in MF vs AMI and HF vs MF. Finally, expression validation and diagnostic capability analysis of selected lncRNAs and mRNAs were performed. Results: Several lncRNA-co-expressed/nearby targeted mRNAs pairs including AC005392.3/AC007278.2-IL18R1, AL356356.1/AL137145.2-PFKFB3 and MKNK1-AS1/LINC01127-IL1R2 were identified. Several signaling pathways including TNF signaling pathway and cytokine-cytokine receptor interaction (involved IL18R1), fructose and mannose metabolism and HIF-1 signaling pathway (involved PFKFB3), hematopoietic cell lineage and fluid shear stress and atherosclerosis (involved IL1R2) and estrogen signaling pathway (involved FKBP5) were screened out. FKBP5, IL1R2, IRAK3, LRG1, RNASE1 and PLAC4 had a potential diagnostic value for HF.

2021-07-13 | GSE168281 | GEO

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