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Upregulation of bfl-1 is a potential mechanism of chemoresistance in B-cell chronic lymphocytic leukaemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2007 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 97, no 6, 769-777 p.Article in journal (Refereed) Published
Abstract [en]

B-cell chronic lymphocytic leukaemia (B-CLL) is characterised by the progressive accumulation of monoclonal CD5+ B cells. In a previous study, we have analysed the expression profile of apoptosis-regulating genes using a cDNA-based microarray and found overexpression of the antiapoptotic bcl-2 family member, bfl-1, in B-CLL cells with an apoptosis-resistant phenotype. In this study, bfl-1 mRNA levels have been determined by competitive PCR in an extended population of B-CLL patients to characterise its role in disease progression and development of chemoresistance. bfl-1 levels were significantly higher in patients with no response (NR) to last chemotherapy than in patients responding (partial response (PR)) to last chemotherapy (P<0.05) and in patients who had not required treatment (P<0.05). We found no correlation between bfl-1 mRNA levels and disease progression, IGHV mutational status or other clinical parameters. In addition, bfl-1 mRNA levels were inversely correlated with apoptotic response to in vitro fludarabine treatment of B-CLL cells. Specific downregulation of bfl-1 using siRNA induced apoptosis in resistant cells. Our data suggest that bfl-1 contributes to chemoresistance and might be a therapeutic target in B-CLL.

Place, publisher, year, edition, pages
2007. Vol. 97, no 6, 769-777 p.
Keyword [en]
Apoptosis, B-CLL, Bfl-1, Chemoresistance
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-13000DOI: 10.1038/sj.bjc.6603951ISI: 000249392100011PubMedID: 17726463OAI: oai:DiVA.org:uu-13000DiVA: diva2:40770
Available from: 2008-01-20 Created: 2008-01-20 Last updated: 2011-01-25Bibliographically approved
In thesis
1. 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 537
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
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)
Available from: 2010-04-07 Created: 2010-03-11 Last updated: 2010-04-07Bibliographically approved

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