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Telomere length as prognostic parameter in chronic lymphocytic leukemia
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. (Göran Roos)
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 [en]
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: urn:nbn:se:umu:diva-39463ISBN: 978-91-7459-138-5 (print)OAI: oai:DiVA.org:umu-39463DiVA: diva2:392779
Public defence
2011-02-18, E04, Norrlands Universitetssjukhus, Byggnad 6E, Umeå, 23:06 (Swedish)
Opponent
Supervisors
Available from: 2011-02-01 Created: 2011-01-27 Last updated: 2011-02-01Bibliographically approved
List of papers
1. Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status
Open this publication in new window or tab >>Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status
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2005 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, no 12, 4807-4812 p.Article in journal (Refereed) Published
Abstract [en]

B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes.

Keyword
Adult, Aged, Aged; 80 and over, Blotting; Southern, Female, Genes; Immunoglobulin, Humans, Immunoglobulin Heavy Chains/*genetics, Immunophenotyping, In Situ Hybridization; Fluorescence, Leukemia; Lymphocytic; Chronic/*diagnosis/*genetics, Lymph Nodes/pathology, Male, Middle Aged, Models; Statistical, Mutation, Polymerase Chain Reaction, Prognosis, Reverse Transcriptase Polymerase Chain Reaction, Telomere/*ultrastructure, Time Factors, Treatment Outcome
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-15407 (URN)10.1182/blood-2004-11-4394 (DOI)15746080 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
2. Telomere length and correlation with histopathogenesis in B-cell leukemias/lymphomas
Open this publication in new window or tab >>Telomere length and correlation with histopathogenesis in B-cell leukemias/lymphomas
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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.

Keyword
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:nbn:se:umu:diva-7565 (URN)10.1111/j.1600-0609.2007.00817.x (DOI)17286609 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
3. Short telomeres are associated with genetic complexity, high risk genomic aberrations, and short survival in chronic lymphocytic leukemia
Open this publication in new window or tab >>Short telomeres are associated with genetic complexity, high risk genomic aberrations, and short survival in chronic lymphocytic leukemia
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2008 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, no 4, 2246-2252 p.Article in journal (Refereed) Published
Abstract [en]

Telomere length is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and clinical course in B-cell chronic lymphocytic leukemia (B-CLL). In a B-CLL cohort of 152 patients, we analyzed telomere length, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression to study the prognostic impact and associations among these factors. An inverse correlation existed between telomere length and IGHV homology (P < .001), CD38 (P < .001), and ZAP-70 expression (P = .01). Patients with telomere lengths below median (ie, "short telomeres") and above median (ie, "long telomeres") had similar incidences of genomic aberrations (74% vs 68%), 13q– (57% vs 49%), and +12q (5% vs 12%). In contrast, 13q– as a single aberration was more frequent in patients with long telomeres (51% vs 21%; P = .006), whereas 11q– (27% vs 9%; P = .014), 17p– (17% vs 0%; P < .001), and 2 or more genomic aberrations (39% vs 8%; P < .001) were more frequent in patients with short telomeres. Compared with patients with long telomeres, treatment-free survival (TFS) and overall survival (OS) was significantly shorter (P < .001 and P = .015, respectively) in the group with short telomeres, and telomere length was an independent prognostic indicator for TFS. These observations have biological and prognostic implications in B-CLL.

National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-7568 (URN)18045969 (PubMedID)
Available from: 2009-01-13 Created: 2009-01-13 Last updated: 2017-12-14Bibliographically approved
4. Telomere length is a robust prognostic marker in early chronic lymphocytic leukemia
Open this publication in new window or tab >>Telomere length is a robust prognostic marker in early chronic lymphocytic leukemia
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(English)Manuscript (preprint) (Other academic)
Keyword
chronic lymphocytic leukemia, telomere length, longitudinal sampling, prognosis
Identifiers
urn:nbn:se:umu:diva-39559 (URN)
Available from: 2011-02-01 Created: 2011-02-01 Last updated: 2011-02-01Bibliographically approved

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