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Association between telomere length and V-H gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2003 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 4, 593-598 p.Article in journal (Refereed) Published
Abstract [en]

The immunoglobulin V-H gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL) into two entities with a different clinical course. Cases with unmutated V-H genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated VH genes, that is, post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and VH gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between VH gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 63 kbp). Shorter telomeres also constituted a subgroup with a worse prognosis than cases with longer telomeres (median survival 59 vs 159 months), Furthermore, the I-g gene sequence data revealed that samples with high mutations frequency (> 6%) had long telomeres (similar to 8 kbp). Thus, both the telomere and VH gene mutation status in CLL appear linked, which may reflect the proliferative history of the clonal cells with regard to the GC reaction. (C) 2003 Cancer Research UK.

Place, publisher, year, edition, pages
London: Nature Publishing Group, 2003. Vol. 88, no 4, 593-598 p.
Keyword [en]
telomere length, immunoglobulin gene, somatic hypermutation, chronic lymphocytic leukaemia, prognosis
National Category
Cancer and Oncology
URN: urn:nbn:se:umu:diva-5079DOI: 10.1038/sj.bjc.6600763ISI: 000181535200017OAI: diva2:144446
Available from: 2003-06-26 Created: 2003-06-26 Last updated: 2014-04-25Bibliographically approved
In thesis
1. Telomere analysis of normal and neoplastic hematopoietic cells: studies focusing on fluorescence in situ hybridization and flow cytometry
Open this publication in new window or tab >>Telomere analysis of normal and neoplastic hematopoietic cells: studies focusing on fluorescence in situ hybridization and flow cytometry
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The telomeres are specialized structures at the end of the chromosomes composed of the repeated DNA sequence (TTAGGG)n and specific proteins bound to the DNA. The telomeres protect the chromosomes from degradation and end to end fusions. Due to the end-replication problem, the telomeric DNA shortens every cell division, forcing the cells into senescence at a critical telomere length. This process can be counteracted by activating a specialized enzyme, telomerase, which adds telomeric repeats to the chromosome ends leading to an extended or infinite cellular life span. Telomerase activity is absent in most somatic tissues but is found in germ cells, stem cells, activated lymphocytes and the vast majority of tumor cells and permanent cell lines. Hence, telomerase has been suggested as a target for cancer treatment as malignant cells almost exclusively express the enzyme and in that context telomere length measurements will be of great importance.

Telomere length is traditionally measured with a Southern blot based technique. A new method for telomere analysis of cells in suspension, called flow-FISH, was developed based on fluorescence in situ hybridization using a telomeric peptide nucleic acid (PNA) probe,

DNA staining with propidium iodide and quantification by flow cytometry. Flow-FISH had high reproducibility and the telomere length measurements showed good correlation with Southern blotting results. The flow-FISH technique also allows studies of cells in specific phases of the cell cycle and the replication timing of telomeric, centromeric and other repetitive sequences were analyzed in a number of cells. Like previous studies, centromeres were shown to replicate late in S phase while the telomere repeats were found to replicate early in S phase or concomitant with the bulk DNA, which is opposite to the patterns described in yeast.

In benign immunopurified lymphocytes from tonsils, high telomerase activity was found in germinal center (GC) B cells. This population also had high hTERT mRNA levels and displayed a telomere elongation as shown by flow-FISH and Southern blotting. Combined immunophenotyping and flow-FISH on unpurified tonsil cells confirmed the results.

Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, can be divided into pre-GC CLL, characterized by unmutated immunoglobulin VH genes and worse prognosis, and post-GC CLL, with mutated VH genes and better prognosis. In 61 cases of CLL, telomere length was measured with Southern blotting and VH gene mutation status was analyzed. A new association was found between VH mutation status and telomere length, where cases with longer telomeres and mutated VH genes (post-GC CLL) had better prognosis

than CLL with short telomeres and unmutated VH genes (pre-GC CLL). A larger study of 112 CLL cases was performed using flow-FISH. The same correlation between telomere length and VH mutation status was found but gender seemed to be of importance as telomere length was a significant prognostic factor for the male CLL patients but not in the female group. Age of the patients and spread of disease seemed to affect the prognostic value of VH gene mutation status.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2003. 66 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 840
Biomedicine, telomere, telomerase, fluorescence in situ hybridization, flow cytometry, flow-FISH, replication timing, chronic lymphocytic leukemia, immunoglobulin gene, prognosis, Biomedicin
National Category
Microbiology in the medical area
Research subject
Medical Cell Biology
urn:nbn:se:umu:diva-76 (URN)91-7305-444-5 (ISBN)
Public defence
2003-05-23, Betula, 6M, Umeå, 09:00
Available from: 2003-06-26 Created: 2003-06-26Bibliographically approved

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