title: Immortalization of T-cells is accompanied by gradual changes in CpG methylation resulting in a profile resembling a subset of T-cell leukemias.
abstract: We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.
authors: Department of Medical Biosciences, Umeå University, SE-90185 Umeå, Sweden. Electronic address: sofie.degerman@medbio.umu.se.
authors: Sofie
authors: S
authors: Degerman
authors: Department of Medical Biosciences, Umeå University, SE-90185 Umeå, Sweden; Department of Mathematics and Mathematical Statistics, Umeå University, SE-90185 Umeå, Sweden.
authors: Mattias
authors: M
authors: Landfors
authors: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, 02-781 Warsaw, Poland.
authors: Jan Konrad
authors: JK
authors: Siwicki
authors: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors: John
authors: J
authors: Revie
authors: Department of Medical Biosciences, Umeå University, SE-90185 Umeå, Sweden.
authors: Magnus
authors: M
authors: Borssén
authors: Department of Medical Biosciences, Umeå University, SE-90185 Umeå, Sweden.
authors: Emma
authors: E
authors: Evelönn
authors: Department of Medical Biosciences, Umeå University, SE-90185 Umeå, Sweden.
authors: Erik
authors: E
authors: Forestier
authors: Department of Medical Genetics, Children's Memorial Health Institute, 04-730 Warsaw, Poland.
authors: Krystyna H
authors: KH
authors: Chrzanowska
authors: Department of Mathematics and Mathematical Statistics, Umeå University, SE-90185 Umeå, Sweden; Computational Life Science Cluster, Umeå University, SE-90185 Umeå, Sweden.
authors: Patrik
authors: P
authors: Rydén
authors: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors: W Nicol
authors: WN
authors: Keith
authors: Department of Medical Biosciences, Umeå University, SE-90185 Umeå, Sweden.
authors: Göran
authors: G
authors: Roos
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks; D006801:Humans; D015458:Leukemia, T-Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D015203:Reproducibility of Results; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology