Sézary syndrome originates from heavily mutated hematopoietic progenitors
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ABSTRACT:
PROVIDER: PRJNA914040 | ENA |
REPOSITORIES: ENA
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Project description:Sézary syndrome originates from heavily mutated hematopoietic progenitors
| PRJNA914039 | ENA
Project description:The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains unclear. Using single-cell RNA or T-cell receptor (TCR) sequencing of 32 619 CD3+CD4+ and CD26+/CD7+ and 29 932 CD3+CD4+ and CD26-/CD7- lymphocytes from the peripheral blood of 7 patients with CTCL, coupled to single-cell ATAC-sequencing of 26,411 CD3+CD4+ and CD26+/CD7+ and 33 841 CD3+CD4+ and CD26-/CD7- lymphocytes, we show that tumor cells in Sézary syndrome and mycosis fungoides (MF) exhibit different phenotypes and trajectories of differentiation. When compared to MF, Sézary cells exhibit narrower repertoires of TCRs and exhibit clonal enrichment. Surprisingly, we identified ≥200 mutations in hematopoietic stem cells from multiple patients with Sézary syndrome. Mutations in key oncogenes were also present in peripheral Sézary cells, which also showed the hallmarks of recent thymic egression. Together our data suggest that CTCL arises from mutated lymphocyte progenitors that acquire TCRs in the thymus, which complete their malignant transformation in the periphery.
| S-EPMC10514084 | biostudies-literature
Project description:BLUEPRINT hematopoietic progenitors
| PRJNA343828 | ENA
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
2025-02-07 | GSE273693 | GEO
Project description:This study used tumour and paired normal samples from 28 Sézary Syndrome (SS) patients to define recurrent regions of chromosomal aberrations. Our data identified recurrent losses of 17p13.2-p11.2 and 10p12.1-q26.3 occurring in 71 and 68% of cases respectively; common gains were detected for 17p11.2-q25.3 (64%) and chromosome 8/8q (50%). Moreover, we identified novel genomic lesions recurring in more than 30% of tumours: loss of 9q13-q21.33 and gain of 10p15.3-10p12.2. In the Sézary Syndrome cases analysed, we could find several small and few large Uniparental Disomies involving interstitial or telomeric regions of LOH occurring mainly for chromosome 10 and to a lesser extent for chromosome 9 and 17. In the attempt to correlate Copy Number data and clinical parameters we find a relationship between complex pattern of chromosomal aberrations, involving at least three recurrent Copy Number alterations, and shorter survival. Integrating mapping and transcriptional data we were able to identify a total of 113 deregulated transcripts in aberrant chromosomal regions that included cancer related genes such as members of the NF-kB pathway (BAG4, BTRC, NKIRAS2, PSMD3, TRAF2) that might explain its constitutive activation in CTCL. Matching this list of genes with those discriminating patients with different survival times we identify several common candidates that might exert critical roles in Sézary Syndrome, like BUB3 and PIP5K1B.
2009-09-30 | GSE17595 | GEO
Project description:This study used tumour and paired normal samples from 28 Sézary Syndrome (SS) patients to define recurrent regions of chromosomal aberrations. Our data identified recurrent losses of 17p13.2-p11.2 and 10p12.1-q26.3 occurring in 71 and 68% of cases respectively; common gains were detected for 17p11.2-q25.3 (64%) and chromosome 8/8q (50%). Moreover, we identified novel genomic lesions recurring in more than 30% of tumours: loss of 9q13-q21.33 and gain of 10p15.3-10p12.2. In the Sézary Syndrome cases analysed, we could find several small and few large Uniparental Disomies involving interstitial or telomeric regions of LOH occurring mainly for chromosome 10 and to a lesser extent for chromosome 9 and 17. In the attempt to correlate Copy Number data and clinical parameters we find a relationship between complex pattern of chromosomal aberrations, involving at least three recurrent Copy Number alterations, and shorter survival. Integrating mapping and transcriptional data we were able to identify a total of 113 deregulated transcripts in aberrant chromosomal regions that included cancer related genes such as members of the NF-kB pathway (BAG4, BTRC, NKIRAS2, PSMD3, TRAF2) that might explain its constitutive activation in CTCL. Matching this list of genes with those discriminating patients with different survival times we identify several common candidates that might exert critical roles in Sézary Syndrome, like BUB3 and PIP5K1B.
2009-09-30 | GSE17601 | GEO
Project description:Disease frameshift mutations of calreticulin (CALR) are the second most prevalent driver mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF). To identify potential targeted therapies for CALR mutated myeloproliferative neoplasms, we aimed to search for small molecule drugs that selectively inhibit the growth of CALR mutated cells using high-throughput drug screening. We investigated 89,172 compounds using isogenic cell lines and identified several hits targeting the ATR-CHK1 pathway. The selective inhibitory effect of these candidate compounds was validated in a co-culture assay of CALR mutated and wild type cells. Of the tested hit compounds, CHK1 inhibitors potently depleted CALR mutated cells, allowing CALR wild type cell dominance in the co-culture over time. Neither CALR deficient cells nor JAK2V617F mutated cells showed hypersensitivity to the drug treatment, suggesting that the vulnerability to ATR-CHK1 inhibition is specifically caused by the oncogenic activation by the mutant CALR. CHK1 inhibitors induced replication stress in CALR mutated cells revealed by elevated pan-nuclear staining for γH2AX and hyperphosphorylation of RPA2. They also promoted S-phase cell cycle arrest and blocked the completion of DNA replication in CALR mutated cells. Transcriptomic and phosphoproteomic analyses revealed a replication stress signature caused by the oncogenic CALR mutation, suggesting an intrinsic vulnerability of these cells to CHK1 perturbation. This study indicates that ATR-CHK1 pathway is a potential therapeutic target in CALR mutated hematopoietic cells.
2021-09-07 | PXD026803 | Pride
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.
2022-12-31 | GSE192836 | GEO
Project description:HDAC10 and Its Implications in Sézary Syndrome Pathogenesis
| PRJNA1142865 | ENA
Project description:mass spectrometry analysis of aged and adult hematopoietic stem cells, multipotent progenitors and oligopotent progenitors
2021-07-24 | PXD017442 | Pride