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The BCL-2 promoter (-938C>A) polymorphism does not predict clinical outcome in chronic lymphocytic leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2008 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 22, no 2, 339-343 p.Article in journal (Refereed) Published
Abstract [en]

The (-938C>A) polymorphism in the promoter region of the BCL-2 gene was recently associated with inferior time to treatment and overall survival in B-cell chronic lymphocytic leukemia (CLL) patients displaying the -938A/A genotype and may thus serve as an unfavorable genetic marker in CLL. Furthermore, the -938A/A genotype was associated with increased expression of Bcl-2. To investigate this further, we analyzed the -938 genotypes of the BCL-2 gene in 268 CLL patients and correlated data with treatment status, overall survival and known prognostic factors, for example, Binet stage, immunoglobulin heavy-chain variable (IGHV) mutational status and CD38 expression. In contrast to the recent report, the current cohort of CLL patients showed no differences either in time to treatment or overall survival in relation to usage of a particular genotype. In addition, no correlation was evident between the (-938C>A) genotypes and IGHV mutational status, Binet stage or CD38. Furthermore, the polymorphism did not appear to affect the Bcl-2 expression at the RNA level. Taken together, our data do not support the use of the (-938C>A) BCL-2 polymorphism as a prognostic marker in CLL and argue against its postulated role in modulating Bcl-2 levels.

Place, publisher, year, edition, pages
2008. Vol. 22, no 2, 339-343 p.
Keyword [en]
chronic lymphocytic leukemia, BCL-2 promoter polymorphism, immunoglobulin heavy-chain variable gene mutation status, Binet stage, CD38, prognosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-13004DOI: 10.1038/sj.leu.2405042ISI: 000253166900015PubMedID: 18046447OAI: oai:DiVA.org:uu-13004DiVA: diva2:40774
Available from: 2008-01-20 Created: 2009-01-12 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
Open this publication in new window or tab >>Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL.

In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL.

In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results.

In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 77 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 507
Keyword
chronic lymphocytic leukemia, prognostic markers, single nucleotide polymorphisms, RNA-based markers
National Category
Medical Genetics Genetics Medical Genetics Biomedical Laboratory Science/Technology Cancer and Oncology Hematology
Research subject
Clinical Genetics; Molecular Medicine; Oncology; Medicine; Medical Genetics
Identifiers
urn:nbn:se:uu:diva-110371 (URN)978-91-554-7677-9 (ISBN)
Public defence
2010-01-20, Rudbecksalen, Rudbeck Laboratory C11, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2009-12-22 Created: 2009-11-12 Last updated: 2011-03-04Bibliographically approved
2. In Vitro Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia
Open this publication in new window or tab >>In Vitro Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic lymphocytic leukemia (CLL) is a heterogeneous malignancy displaying varying clinical outcome, where molecular markers today can divide patients into prognostic subgroups. Despite the introduction of new agents for treatment, remissions are usually not sustained in CLL and resistance towards treatment can partly be explained by aberrant apoptosis. The aim of this thesis was to find new drugs for CLL patients resistant to conventional therapy and to analyze genes involved in apoptosis within different prognostic subgroups.

In paper I-II, the in vitro activity of substances was investigated using the fluorometric microculture cytotoxicity assay (FMCA). When evaluating rapamycin (paper I), an inhibitor of mTOR, in 97 tumor samples from different entities, CLL was found to be one of the most sensitive tumor types. Combination experiments on patient CLL cells indicated that rapamycin acted synergistically with the CLL drugs vincristine and chlorambucil.

An investigation of 20 anti-cancer agents in cells from 40 CLL patients (paper II) revealed that prednisolone and rolipram displayed high activity in poor-prognostic patients, in particular IGHV unmutated CLL. Furthermore, when used in combination these agents were found to produce a synergistic effect.

In paper III, the anti-apoptotic BCL2 family member BFL1 was evaluated in 37 CLL cases. Levels of BFL1 were higher in fludarabine-resistant patients compared to fludarabine-sensitive patients. In addition, the high expression of BFL1 inversely correlated to fludarabine-induced apoptosis in CLL cells.

A single nucleotide polymorphism in the anti-apoptotic BCL2 gene (-938C>A) has been suggested as a novel poor-prognostic marker in CLL. In paper IV, we investigated this BCL2 polymorphism in 268 CLL patients and correlated genotypes to clinical data. However, no association could be confirmed between this polymorphism and clinical outcome or established prognostic markers.

In conclusion, this thesis has shown that rapamycin is a potential drug for treatment in CLL. Furthermore, prednisolone and rolipram were identified as interesting candidates for treatment of poor-prognostic patients. Finally, the anti-apoptotic protein BFL1 may contribute to chemoresistance and hence represents a potential therapeutic target in CLL, whereas from our data, the BCL2 -938C>A polymorphism does not appear to have any prognostic significance.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 537
Keyword
chronic lymphocytic leukemia, in vitro drug sensitivity, apoptosis, prognostic markers
National Category
Medical Genetics Hematology Medical Genetics Medical and Health Sciences Medical Genetics
Research subject
Medical Science; Clinical Genetics; Molecular Genetics; Medical Genetics; Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-120299 (URN)978-91-554-7750-9 (ISBN)
Public defence
2010-04-29, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2010-04-07 Created: 2010-03-11 Last updated: 2010-04-07Bibliographically approved

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Kaderi, Mohd ArifinNorberg, MariaMurray, FionaSundström, ChristerRosenquist, Richard

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