Epigenome-wide analysis of T-cell large granular lymphocytic leukemia identifies BCL11B as a potential biomarker
| العنوان: | Epigenome-wide analysis of T-cell large granular lymphocytic leukemia identifies BCL11B as a potential biomarker |
|---|---|
| المؤلفون: | Patricia Johansson, Teresa Laguna, Julio Ossowski, Vera Pancaldi, Martina Brauser, Ulrich Dührsen, Lara Keuneke, Ana Queiros, Julia Richter, José I. Martín-Subero, Reiner Siebert, Brigitte Schlegelberger, Ralf Küppers, Jan Dürig, Eva M. Murga Penas, Enrique Carillo-de Santa Pau, Anke K. Bergmann |
| المساهمون: | Barcelona Supercomputing Center |
| بيانات النشر: | BioMed Central (BMC), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC], DNA methylation, Tumor Suppressor Proteins, Medizin, Pyrosequencing, BCL11B, DNA Methylation, Large granular lymphocytic leukemia, Epigenètica, Leukemia, Large Granular Lymphocytic, Repressor Proteins, Epigenome, Lymphocytic leukemia, T-LGLL, Simulació per ordinador, Genetics, Humans, Gene expression, Molecular Biology, Genetics (clinical), Biomarkers, Developmental Biology, Transcription Factors |
| الوصف: | Background The molecular pathogenesis of T-cell large granular lymphocytic leukemia (T-LGLL), a mature T-cell leukemia arising commonly from T-cell receptor αβ-positive CD8+ memory cytotoxic T cells, is only partly understood. The role of deregulated methylation in T-LGLL is not well known. We analyzed the epigenetic profile of T-LGLL cells of 11 patients compared to their normal counterparts by array-based DNA methylation profiling. For identification of molecular events driving the pathogenesis of T-LGLL, we compared the differentially methylated loci between the T-LGLL cases and normal T cells with chromatin segmentation data of benign T cells from the BLUEPRINT project. Moreover, we analyzed gene expression data of T-LGLL and benign T cells and validated the results by pyrosequencing in an extended cohort of 17 patients, including five patients with sequential samples. Results We identified dysregulation of DNA methylation associated with altered gene expression in T-LGLL. Since T-LGLL is a rare disease, the samples size is low. But as confirmed for each sample, hypermethylation of T-LGLL cells at various CpG sites located at enhancer regions is a hallmark of this disease. The interaction of BLC11B and C14orf64 as suggested by in silico data analysis could provide a novel pathogenetic mechanism that needs further experimental investigation. Conclusions DNA methylation is altered in T-LGLL cells compared to benign T cells. In particular, BCL11B is highly significant differentially methylated in T-LGLL cells. Although our results have to be validated in a larger patient cohort, BCL11B could be considered as a potential biomarker for this leukemia. In addition, altered gene expression and hypermethylation of enhancer regions could serve as potential mechanisms for treatment of this disease. Gene interactions of dysregulated genes, like BLC11B and C14orf64, may play an important role in pathogenic mechanisms and should be further analyzed. Open Access funding enabled and organized by Projekt DEAL. PJ was funded by IFORES and the Dr. Werner Jackstädt Stiftung. TL and ECdSP received funding from the Spanish Ministry of Science (Plan Nacional I + D+i PID2019-110183RB-C21); RK was supported by the DFG (KU1315/9-2). Peer Reviewed "Article signat per 17 autors/es: Patricia Johansson, Teresa Laguna, Julio Ossowski, Vera Pancaldi, Martina Brauser, Ulrich Dührsen, Lara Keuneke, Ana Queiros, Julia Richter, José I. Martín-Subero, Reiner Siebert, Brigitte Schlegelberger, Ralf Küppers, Jan Dürig, Eva M. Murga Penas, Enrique Carillo-de Santa Pau & Anke K. Bergmann " |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::77e810c4395fb39f67f72e2bc2e7bd69Test https://hdl.handle.net/2117/377614Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....77e810c4395fb39f67f72e2bc2e7bd69 |
| قاعدة البيانات: | OpenAIRE |
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The role of deregulated methylation in T-LGLL is not well known. We analyzed the epigenetic profile of T-LGLL cells of 11 patients compared to their normal counterparts by array-based DNA methylation profiling. For identification of molecular events driving the pathogenesis of T-LGLL, we compared the differentially methylated loci between the T-LGLL cases and normal T cells with chromatin segmentation data of benign T cells from the BLUEPRINT project. Moreover, we analyzed gene expression data of T-LGLL and benign T cells and validated the results by pyrosequencing in an extended cohort of 17 patients, including five patients with sequential samples. Results We identified dysregulation of DNA methylation associated with altered gene expression in T-LGLL. Since T-LGLL is a rare disease, the samples size is low. But as confirmed for each sample, hypermethylation of T-LGLL cells at various CpG sites located at enhancer regions is a hallmark of this disease. The interaction of BLC11B and C14orf64 as suggested by in silico data analysis could provide a novel pathogenetic mechanism that needs further experimental investigation. Conclusions DNA methylation is altered in T-LGLL cells compared to benign T cells. In particular, BCL11B is highly significant differentially methylated in T-LGLL cells. Although our results have to be validated in a larger patient cohort, BCL11B could be considered as a potential biomarker for this leukemia. In addition, altered gene expression and hypermethylation of enhancer regions could serve as potential mechanisms for treatment of this disease. Gene interactions of dysregulated genes, like BLC11B and C14orf64, may play an important role in pathogenic mechanisms and should be further analyzed. Open Access funding enabled and organized by Projekt DEAL. PJ was funded by IFORES and the Dr. Werner Jackstädt Stiftung. 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