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Spontaneously immortalized human T lymphocytes develop gain of chromosomal region 2p13-24 as an early and common genetic event
Vise andre og tillknytning
2004 (engelsk)Inngår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 41, nr 2, s. 133-144Artikkel i tidsskrift (Fagfellevurdert) Published
sted, utgiver, år, opplag, sider
2004. Vol. 41, nr 2, s. 133-144
Emneord [en]
Cell Line; Transformed, Chromosome Aberrations, Chromosome Banding, Chromosome Mapping, Chromosomes; Human; Pair 2/*genetics, Chromosomes; Human; Pair 8/genetics, Humans, In Situ Hybridization; Fluorescence, Karyotyping, Neoplasms/genetics, T-Lymphocytes/*physiology
HSV kategori
Forskningsprogram
patologi
Identifikatorer
URN: urn:nbn:se:umu:diva-15213DOI: 10.1002/gcc.20059PubMedID: 15287026OAI: oai:DiVA.org:umu-15213DiVA, id: diva2:154885
Tilgjengelig fra: 2008-01-11 Laget: 2008-01-11 Sist oppdatert: 2018-06-09bibliografisk kontrollert
Inngår i avhandling
1. The immortalization process of T cells: with focus on the regulation of telomere length and telomerase activity
Åpne denne publikasjonen i ny fane eller vindu >>The immortalization process of T cells: with focus on the regulation of telomere length and telomerase activity
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Cellular immortalization is a major hallmark of cancer and is a multi-step process that requires numerous cell-type specific changes, including inactivation of control mechanisms and stabilization of telomere length. The telomeres at the chromosome ends are essential for genomic stability, and limit the growth potential of most cells. With each cell division, telomeres are shortened. Short telomeres may induce an irreversible growth arrest stage called senescence, or a growth crisis stage characterized by high genomic instability and cell death. Only very rarely do cells escape from crisis and become immortal, a stage that has been associated with the activation of the telomerase enzyme which can elongate and stabilize the telomeres.

The processes leading to senescence bypass, growth crisis escape and finally immortalization are only beginning to be elucidated. Most of our knowledge of the immortalization process is based on analyses of human fibroblast and epithelial cell cultures immortalized by genetic modification. In this thesis, spontaneously immortalized human T lymphocytes derived from patients with Nijmegen Breakage Syndrome and a healthy individual were used to identify critical events for senescence bypass and immortalization. Genetic analysis showed a clonal progression and non-random genetic changes including the amplification of chromosomal region 2p13-21 as an early event in the immortalization process. Telomere length gradually shortened at increasing population doublings and growth crisis was associated with critically short telomeres. The clone(s) that escaped growth crisis demonstrated a logarithmic growth curve, very short telomeres and, notably, no increase in telomerase activity or expression of the telomerase catalytic gene, hTERT. Instead, upregulation of telomerase activity and telomere length stabilization were late events in T lymphocyte immortalization. Escape from crisis was associated with downregulation of DNA damage response genes and altered expression of cell cycle regulators and genes controlling the cellular senescence program.

These data indicated that a number of layers of regulation are important in the process of immortalization and to provide further mechanistic detail, epigenetic analysis was carried out. Genome wide methylation array analysis identified early and step-wise methylation changes during the immortalization process. Interestingly, applying these findings to tumors of T cell origin revealed commonly methylated CpG sites in transformed cells. Deregulated gene expression of the polycomb complexes may have contributed to the epigenetic changes observed.

Taken together, our analysis of spontaneously immortalized T cell cultures identified several steps in the immortalization process including genetic, epigenetic, gene expression and telomere/telomerase regulatory events, contributing further insights to the complexity of cancer cell immortalization.

sted, utgiver, år, opplag, sider
Umeå: Umeå university, 2010. s. 60
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1347
Emneord
immortalization, senescence, T cells, Nijmegen breakage syndrome, telomere, telomerase, hTERT, generic aberrations, methylation
HSV kategori
Forskningsprogram
patologi
Identifikatorer
urn:nbn:se:umu:diva-33466 (URN)978-91-7459-007-4 (ISBN)
Disputas
2010-05-21, Betula, Norrlands Universitetssjukhus, Byggnad 6M,, UMEÅ, 09:00 (engelsk)
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Veileder
Tilgjengelig fra: 2010-04-30 Laget: 2010-04-26 Sist oppdatert: 2010-04-30bibliografisk kontrollert

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Degerman, SofieRoos, Göran

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