Disruption of direct 3D telomere-TRF2 interaction through two molecularly disparate mechanisms is a hallmark of primary Hodgkin and Reed-Sternberg cells
| Autor: | Tina Haliotis, Daniel Lichtensztejn, Sabine Mai, Nathalie A. Johnson, Hans Knecht |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adult Male In situ hybridization Biology Pathology and Forensic Medicine Telomere organization Cell Line 03 medical and health sciences Young Adult 0302 clinical medicine Multinucleate medicine Humans Telomeric Repeat Binding Protein 2 Reed-Sternberg Cells Molecular Biology Lymph node Aged Aged 80 and over Cell Biology Middle Aged Telomere medicine.disease Molecular biology Hodgkin Disease Lymphoma 030104 developmental biology medicine.anatomical_structure Reed–Sternberg cell Cell culture 030220 oncology & carcinogenesis Female |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology. 97(7) |
| ISSN: | 1530-0307 |
| Popis: | In classical Hodgkin's lymphoma (cHL), specific changes in the 3D telomere organization cause progression from mononuclear Hodgkin cells (H) to multinucleated Reed-Sternberg cells (RS). In a post-germinal center B-cell in vitro model, permanent latent membrane protein 1 (LMP1) expression, as observed in Epstein-Barr virus (EBV)-associated cHL, results in multinuclearity and complex chromosomal aberrations through downregulation of key element of the shelterin complex, the telomere repeat binding factor 2 (TRF2). Thus, we hypothesized that the three-dimensional (3D) telomere-TRF2 interaction was progressively disturbed during transition from H to RS cells. To this end, we developed and applied for the first time a combined quantitative 3D TRF2-telomere immune fluorescent in situ hybridization (3D TRF2/Telo-Q-FISH) technique to monolayers of primary H and RS cells, and adjacent benign internal control lymphocytes of lymph node biopsy suspensions from diagnostic lymph node biopsies of 14 patients with cHL. We show that H and RS cells are characterized by two distinct patterns of disruption of 3D telomere-TRF2 interaction. Disruption pattern A is defined by massive attrition of telomere signals and a considerable increase of TRF2 signals not associated with telomeres. This pattern is restricted to EBV-negative cHL. Disruption pattern B is defined by telomere de-protection due to an impressive loss of TRF2 signals, physically linked to telomeres. This pattern is typical of, but is not restricted to, LMP1+EBV-associated cHL. In the disruption pattern B group, so-called 'ghost' end-stage RS cells, void of both TRF2 and telomere signals, were identified, whether or not associated with EBV. Our findings demonstrate that two molecularly disparate mechanisms converge on the level of 3D telomere-TRF2 interaction in the formation of RS cells. |
| Databáze: | OpenAIRE |
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