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Telomere length and correlation with histopathogenesis in B-cell leukemias/lymphomas
Department of Genetics and Pathology, Uppsala University, Uppsala.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala.
Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala.
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2007 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 78, no 4, 283-289 p.Article in journal (Refereed) Published
Abstract [en]

Telomere length was recently reported to correlate with cellular origin of B-cell malignancies in relation to the germinal center (GC). In this report, we measured telomere length by quantitative-PCR in 223 B-cell lymphomas/leukemias and correlated results with immunoglobulin (Ig) mutation status and immunostainings for GC/non-GC subtypes of diffuse large B-cell lymphoma (DLBCL). Shortest telomeres were found in Ig-unmutated chronic lymphocytic leukemia (CLL) [median telomere to single copy gene value (T/S) 0.33], differing significantly to Ig-mutated CLL (0.63). Contrary to this, mantle cell lymphomas (MCLs) exhibited similar telomere lengths regardless of Ig mutation status (0.47). Telomere length differed significantly between GC-like (0.73) and non-GC-like DLBCLs (0.43), and follicular lymphomas (FLs) had shorter telomeres (0.53) than GC-DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres (0.62) than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. We conclude that although DLBCL and CLL subsets can be clearly distinguished, telomere length reflects many parameters and may not simply correlate with GC-related origin.

Place, publisher, year, edition, pages
2007. Vol. 78, no 4, 283-289 p.
Keyword [en]
DNA Mutational Analysis, Germinal Center/*pathology, Humans, Immunoglobulins/*genetics, Leukemia; B-Cell/diagnosis/*genetics, Lymphoma; B-Cell/diagnosis/*genetics, Mutation, Reverse Transcriptase Polymerase Chain Reaction/methods, Sensitivity and Specificity, Telomere/*genetics
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-7565DOI: 10.1111/j.1600-0609.2007.00817.xPubMedID: 17286609OAI: oai:DiVA.org:umu-7565DiVA: diva2:147236
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Telomere length as prognostic parameter in chronic lymphocytic leukemia
Open this publication in new window or tab >>Telomere length as prognostic parameter in chronic lymphocytic leukemia
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia among the adult population in western countries and accounts for 30-40% of all leukemias. With survival time ranging from months to decades, the clinical course of individual CLL patients is highly variable. This heterogeneity and in the end the need for means to identify the patients with less favorable disease has encouraged the search for biomarkers that can predict the prognosis.

Telomeres are repetitive structures protecting the chromosomal endings and shorten at each cell division. Telomere length (TL) has been indicated as a prognostic factor both in hematological malignancies and solid tumors. In B-CLL, TL is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and with clinical course. In the present thesis the main aim was to evaluate TL as a biomarker in B-CLL using a quantitative PCR-based method for TL determination.

In paper I, TL was shown to be a prognostic factor for stage A and stage B/C patients, whereas IGHV mutation status predicted outcome only in stage A patients. Moreover, IGHV mutated CLL cases were subdivided by TL into two groups with different prognosis, a subdivision not seen for unmutated cases. Interestingly, the IGHV-mutated group with short telomeres had en overall survival close to that of the unmutated cases. Thus, a combination of IGHV mutation status and telomere length gave an improved subclassification of CLL identifying previously unrecognized patient groups with different outcomes.

TL correlates with cellular origin of B-cell malignancies in relation to the germinal center (GC). In paper II different B-cell lymphoma/leukemia subtypes were analyzed. Shortest telomeres were found in IGHV unmutated CLLs, differing significantly from IGHV mutated cases. Contrary to this, mantle cell lymphomas (MCL) demonstrated similar TL regardless of IGHV mutation status. TL differed significantly between GC-like and non-GC-like diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas (FL) had shorter telomeres than GC-like DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. In conclusion, TL seemed not to simply correlate with GC origin.

Paper III presents a B-CLL cohort assessed for TL, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression. An inverse correlation existed between TL and IGHV homology, CD38 and ZAP-70 expression. The presence of genomic aberrations was similar among patients regardless of TL. In contrast, 13q deletion, a favorable biomarker, was more frequent in patients with long telomeres, while 11q and 17p deletions (markers of less favorable outcome) were more frequent in the subgroup with short telomeres.

In paper IV a large group of mainly indolent CLL cases from a population based cohort was studied again showing an association between TL and prognosis, especially in “good” prognosis cases as defined by other biomarkers. Multivariate analysis indicated a strong connection between IGHV mutation status, lipoprotein lipase (LPL) expression and TL. A comparison of TL in diagnostic and follow up samples demonstrated a significant correlation, and also in the follow samples TL constituted a significant biomarker for survival.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2011. 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1399
Keyword
telomere length, chronic lymphocytic leukemia, prognosis, longitudinal sampling, genomic aberrations, IGHV, CD38, ZAP70, prognostic factors
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-39463 (URN)978-91-7459-138-5 (ISBN)
Public defence
2011-02-18, E04, Norrlands Universitetssjukhus, Byggnad 6E, Umeå, 23:06 (Swedish)
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Available from: 2011-02-01 Created: 2011-01-27 Last updated: 2011-02-01Bibliographically approved

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