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Epigenome-wide analysis of T-cell large granular lymphocytic leukemia identifies BCL11B as a potential biomarker.

Authors
  • Johansson, Patricia1
  • Laguna, Teresa2
  • Ossowski, Julio3, 4
  • Pancaldi, Vera5, 6
  • Brauser, Martina7
  • Dührsen, Ulrich8
  • Keuneke, Lara3
  • Queiros, Ana9
  • Richter, Julia10
  • Martín-Subero, José I9, 11
  • Siebert, Reiner3, 12
  • Schlegelberger, Brigitte4
  • Küppers, Ralf7
  • Dürig, Jan13
  • Murga Penas, Eva M3
  • Carillo-de Santa Pau, Enrique14
  • Bergmann, Anke K4
  • 1 Faculty of Medicine, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Virchowstr. 177, 45122, Essen, Germany. [email protected]. , (Germany)
  • 2 Computational Biology Group, Precision Nutrition and Cancer Research Program, IMDEA Food Institute, 28049, Madrid, Spain. [email protected]. , (Spain)
  • 3 Institute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany. , (Germany)
  • 4 Institute of Human Genetics, Medical School Hannover (MHH), Hannover, Germany. , (Germany)
  • 5 Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, INSERM U1037, 31037, Toulouse, France. , (France)
  • 6 Barcelona Supercomputing Center, 08034, Barcelona, Spain. , (Spain)
  • 7 Faculty of Medicine, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Virchowstr. 177, 45122, Essen, Germany. , (Germany)
  • 8 Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. , (Germany)
  • 9 Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, 08036, Barcelona, Spain. , (Spain)
  • 10 Institute for Pathology, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany. , (Germany)
  • 11 Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain. , (Spain)
  • 12 Institute of Human Genetics, University of Ulm and University Medical Center Ulm, Ulm, Germany. , (Germany)
  • 13 Department of Internal Medicine, University Hospital Essen, St. Josef-Krankenhaus, University Medicine Essen, Essen, Germany. , (Germany)
  • 14 Computational Biology Group, Precision Nutrition and Cancer Research Program, IMDEA Food Institute, 28049, Madrid, Spain. , (Spain)
Type
Published Article
Journal
Clinical Epigenetics
Publisher
Springer-Verlag
Publication Date
Nov 14, 2022
Volume
14
Issue
1
Pages
148–148
Identifiers
DOI: 10.1186/s13148-022-01362-z
PMID: 36376973
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. © 2022. The Author(s).

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