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.
Project description:In CTCL, the ectopic expression of Gametocyte Specific Factor 1 (GTSF1) has emerged as a potential prognostic biomarker. High expression of GTSF1 has been associated with a worse overall prognosis for patients. However, the contribution of GTSF1 to CTCL carcinogenesis remains unknown. We performed a shRNA mediated silencing of GTSF1 in three cell lines representing the most common variants of CTCL: Mac2A, representative of primary cutaneous Anaplastic Large Cell Lymphoma; MyLa 2000, representative of Mycosis Fungoides; and SZ4, representative of Sézary Syndrome. The three cell lines showed different gene expression profiles, signaling the different clinical behaviors of each variant. In Mac2A, silencing of GTSF1 in CTCL led to T cell activation and production of IFNγ and TNFα. This suugests that GTSF1 contributes to carcinogenesis by partially modifying the effector-memory phenotype of the malignant T cells.
Project description:Cutaneous T-cell lymphomas (CTCL) are a group of rare hematological malignancies characterized by infiltration of malignant T-cells into the skin. Two main types of CTCL constitute of Mycosis Fungoides (MF), a more indolent form of the disease, and Sézary Syndrome (SS), the aggressive and leukemic variant with blood involvement. Sézary syndrome presents a significant clinical challenge due to its very aggressive nature, poor prognosis, and treatment resistance, and to date, the disease is known to be uncurable. Histone deacetylase inhibitors have gained attention in CTCL treatment with promising results, but they expose limited specificity and strong side effects. Recent genomic studies underscore the role of epigenetic modifiers in CTCL pathogenesis, prompting an investigation into HDAC10, a member of Class IIb HDACs, in SS. HDAC10 was investigated in different cancers, revealing its involvement in the cell cycle regulation, apoptosis, and autophagy, but its role in CTCL is unknown. In this study we aimed to determine the role of HDAC10 in Sezary Syndrome, focusing on its cellular localization, role in cell growth, and potential therapeutic target. We indicated that HDAC10 is overexpressed in SS patients and located mainly in the cytoplasm. Its overexpression leads to an inhibitory effect on apoptosis progression when exposed to the pro-apoptotic compound Camptothecin (CPT). Knockdown of HDAC10 resulted in reduced cell growth and induction of apoptosis and autophagy, highlighting its potential importance in CTCL pathogenesis. Whole transcriptome analysis indicated that HDAC10 is associated with crucial cancer-related pathways for example hematopoietic cell lineage, PI3K-Akt signaling pathway, pathways in cancer, Ras signaling pathway, MAPK signaling pathway or JAK-STAT signaling pathway, which are critical for the survival and proliferation of malignant T cells. Inhibition of HDAC10 with selective HDAC10i increased the sensitivity of Sézary cells to the pro-apoptotic compound camptothecin (CPT). Our findings demonstrate that HDAC10 plays a key role in the molecular background of Sézary syndrome, highlighting its importance in the cellular mechanisms of the disease
Project description:We performed transcriptome analysis and multimodal data integration of the transcriptome and the microbiome of the skin of Mycosis fungoides Patients.
Project description:FOXM1 is a vital transcription factor associated with proliferation, expressed extensively and dynamically throughout the cell cycle. Its overexpression in mycosis fungoides correlates with a poor prognosis. However, the specific role of FOXM1 in the pathogenesis of mycosis fungoides remains unclear. In this study, we silenced FOXM1 in the MyLa cell line, which is representative of mycosis fungoides, by transducing it with a lentivirus vector containing shRNA targeting the FOXM1 gene. By comparing MyLa cells transduced with scrambled shRNA as the control, we observed distinct gene expression profiles, notably a decrease in the expression of cell cycle-related genes and an increase in apoptosis-related genes. These changes align with the phenotypic alterations of MyLa cells following FOXM1 silencing.