Andersson_et_al_2013
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Emma Andersson
PROVIDER: E-MTAB-2068 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Large lymphocytic leukemia (LGL) is a chronic clonal lymphoproliferative disorder, characterized by expansion of cytotoxic CD8+ T-cells or NK-cells. We compared gene expression of 3 LGL leukemia patients with STAT3 mutation (Patients 1, 2, and 3), 3 LGL leukemia patients with STAT5b mutation (Patients 4, 5, and 6), and 2 LGL leukemia patients without STAT3/STAT5b mutation (Patients 7 and 8) with CD8 and NK-cell samples from healthy controls to assess different gene expression patterns between samples.
2013-04-15 | E-MTAB-1611 | biostudies-arrayexpress
Project description:TCRαβ CD8 large granular lymphocyte (LGL) leukemia is a rare heterogeneous hematological disorder with a chronic disease course that mostly affects elderly. It is generally accepted that LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of dysregulation of mainly the STAT3 but also to some extent the ERK pathway, which are constitutively activated. In approximately 40% of patients this is due to STAT3 activating mutations, but for the other 60% it remains to be elucidated, why the STAT3 pathway is chronically activated. miRNAs are one of the most potent regulators in health and disease and are also linked with various leukemias. Therefore, we hypothesized that aberrant miRNA expression could contribute to dysregulation of the STAT3 pathway. miRNA sequencing in LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miRNA181a. Furthermore, gene set enrichment analysis (GSEA) of miRNA181a implicated its involvement in the STAT3 and ERK1/2 pathways. Phosphoflow analysis of STAT3, ERK1/2 in miR181a-transfected human CD8 T cells revealed that miR181a overexpression results in STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line model, we have now established that miR181a is the common actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition in LGL leukemia patients. Additionally, miR181a induces ERK1/2 phosphorylation by inhibition of DUSP6. Taken together, our data show that miR181a is the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.
2021-12-01 | GSE159878 | GEO
Project description:TCRαβ CD8 large granular lymphocyte (LGL) leukemia is a rare heterogeneous hematological disorder with a chronic disease course that mostly affects elderly. It is generally accepted that LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of dysregulation of mainly the STAT3 but also to some extent the ERK pathway, which are constitutively activated. In approximately 40% of patients this is due to STAT3 activating mutations, but for the other 60% it remains to be elucidated, why the STAT3 pathway is chronically activated. miRNAs are one of the most potent regulators in health and disease and are also linked with various leukemias. Therefore, we hypothesized that aberrant miRNA expression could contribute to dysregulation of the STAT3 pathway. miRNA sequencing in LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miRNA181a. Furthermore, gene set enrichment analysis (GSEA) of miRNA181a implicated its involvement in the STAT3 and ERK1/2 pathways. Phosphoflow analysis of STAT3, ERK1/2 in miR181a-transfected human CD8 T cells revealed that miR181a overexpression results in STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line model, we have now established that miR181a is the common actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition in LGL leukemia patients. Additionally, miR181a induces ERK1/2 phosphorylation by inhibition of DUSP6. Taken together, our data show that miR181a is the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.
2021-12-01 | GSE159819 | GEO
Project description:We used microarrays to expression profile peripheral blood mononuclear cells (PBMCs) from LGL leukemia patients and control subjects to identify survival pathways that render leukemic LGL resistant to activation induced cell death. Experiment Overall Design: Leukemic PBMC RNA from 30 patients was extracted for target preparation and hybridization onto Affymetrix microarrays. We also isolated PBMCs and PBMCs subjected to enrichment for CD8+ cells from control patients. RNA from these cells (naïve or activated with phytohemagglutinin) was extracted for target preparation and hybridization onto Affymetrix microarrays.
2008-06-11 | E-GEOD-10631 | biostudies-arrayexpress
Project description:We used microarrays to expression profile peripheral blood mononuclear cells (PBMCs) from LGL leukemia patients and control subjects to identify survival pathways that render leukemic LGL resistant to activation induced cell death. Keywords: granular lymphocyte leukemia, PBMC
2008-05-01 | GSE10631 | GEO
Project description:Background and methods: T-cell large granular lymphocytosis (T-LGL) is a lymphoproliferative disease usually presenting with cytopenia, and typically characterized by clonal expansion of terminally differentiated effector-memory cytotoxic T lymphocytes (CTLs). Conventional methods including flow cytometry and sequencing of Vb chains provided incomplete signature of TCR repertoire. Efforts to characterize transcriptome of clonal CTLs using whole peripheral blood or after enrichment of specific clones by flow cytometry have not provided satisfying resolution and scale due to heterogeneity among individual patients. We applied single cell TCR-sequencing coupled with single cell RNA sequencing to CD3+ T cells from a relatively large cohort (N=13) of T-LGL patients in a clinical protocol to prospectively test therapy with alemtuzumab in refractory disease, to characterize TCR repertoire and to define pathophysiologic mechanism at the single cell level, and to determine mechanisms of response and non-response to therapy. Results: T cells have less clonal diversity in T-LGL patients, compared with that in healthy donors. TCR repertoires in T-LGLL follow power law distribution but at a larger scale. There are no significant evidence of common TCR clonotypes among T-LGLL patients. TCR usage and T cell activation states shape T cell phenotypes. Cell survival and apoptosis gene programs are deregulated in T-LGL. Immunosuppressive treatment modulates clonality and gene expression in T-LGL. Conclusion: Our work complements and adds to previous modeling of T cell clonal expansion. Single cell sequencing of transcriptomes supports a theory of fluctuation in clone fitness, antigenic and environmental factors in concert with clone-specific and cell-specific germline and somatic genetic factors (HLA and STAT3).
2021-11-22 | GSE168859 | GEO
Project description:Our results suggest that STAT3 can be activated independent of key oncogenic driver mutations in its SH2 domain in a subset of patients with large granular lymphocyte disorders. We examined the gene expression pattern in T-LGL leukemias compared to controls, and the impact of the presence of STAT3 mutations on the transcriptional regulation of a specific set of genes previously described. Mononuclear cells were separated from peripheral blood by density gradient sedimentation (Mediatech, Herndon, VA, USA). LGL cells were separated by flow cytometric sorting using anti-VB and CD8 mAb as described previously. Healthy, donor-derived CD8+CD57+ cells were isolated by flow cytometric sorting using CD3, CD8, and CD57 mAb. Total RNA was extracted from cells using Trizol (Invitrogen, Carlsbad, CA, USA) Phase-Lock gel tubes (Eppendorf, Hamburg, Germany), cleaned RNAeasy columns (Qiagen, Valencia CA, USA), and dissolved diethylpyrocarbonate water. Total cRNA was prepared using the in vitro-transcribed (Affymetrix, Santa Clara, CA, USA) and hybridized to U133 arrays, according to the manufacturer's instructions (Affymetrix). All microarrays were examined for surface defects, grid placement, background intensity, housekeeping gene expression, and a 3:5 ratio of probe from genes of varying length. Expression analysis was conducted using standard Affymetrix analysis software algorithms (Microarray Suite 5.0). Comparative analysis between expression profiles was carried out on GeneSpring' software, Version 7.1 (Agilent, Clara, CA, USA). Scanned images of Affymetrix chips were converted spreadsheet numbers using Affymetrix proprietary GeneChip Operating software (GCOS).
2012-08-02 | E-GEOD-39838 | biostudies-arrayexpress
Project description:Our results suggest that STAT3 can be activated independent of key oncogenic driver mutations in its SH2 domain in a subset of patients with large granular lymphocyte disorders. We examined the gene expression pattern in T-LGL leukemias compared to controls, and the impact of the presence of STAT3 mutations on the transcriptional regulation of a specific set of genes previously described.
2012-08-03 | GSE39838 | GEO
Project description:miR181a is a novel key player in the STAT3 mediated survival network of TCRab CD8+ T-LGL leukemia
| PRJNA670710 | ENA
Project description:Eastern Clinical Oncology Group trial number 5998 determined the efficacy of the immunosupressives methotrexate (step 1) and cylophosphamide (step 2) in the treatment of Large Granular Lymphocyte leukemia. Expression data from pre-treatment samples were evaluated for a priori ability to predict treatment response to Step 1 and for correlation with STAT3 mutation types predictive of response. Method: patient PBMCs from Ficoll, normal patient PBMCS enriched for CD3+/CD8+ or CD3+/CD8+/CD45RA+/CCR7- were extracted in Trizol. Conclusion: A gene expression profile was associated with response to treatment with evidence of particular STAT3 mutations driving this expression profile and response.
2014-12-29 | GSE42664 | GEO