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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4681-4689. Prepublished online as a Blood First Edition Paper on January 28, 2008; DOI 10.1182/blood-2007-11-125278. This Article Full Text (PDF) All Versions of this Article: blood-2007-11-125278v1 111/9/4681    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hewamana, S. Articles by Pepper, C. Search for Related Content PubMed PubMed Citation Articles by Hewamana, S. Articles by Pepper, C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 26, 2007 Accepted January 25, 2008 The NF-B subunit, Rel A, is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukaemia and represents a promising therapeutic target Saman Hewamana, Suhair Alghazal, Thet Thet Lin, Matthew Clement, Chris Jenkins, Monica L Guzman, Craig T. Jordan, Sundar Neelakantan, Peter A Crooks, Alan K Burnett, Guy Pratt, Chris Fegan, Clare Rowntree, Paul Brennan, and Chris Pepper* Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom Department of Medical Biochemistry & Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom Division of Hematology/Oncology, University of Rochester School of Medicine, Rochester, NY, United States Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, United States Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom * Corresponding author; email: peppercj{at}cf.ac.uk. In this study we characterized NF-B subunit DNA binding in CLL samples and demonstrated heterogeneity in basal and inducible NF-B. However, all cases showed higher basal NF-B than normal B-cells. Subunit analysis revealed DNA binding of p50, Rel A and c-Rel in primary CLL cells and Rel A DNA binding was associated with in vitro survival (P=0.01) with high white cell count (P=0.01) and shorter lymphocyte doubling time (P=0.01). NF-B induction following in vitro stimulation with anti-IgM was associated with increased in vitro survival (P<0.0001) and expression of the signaling molecule ZAP-70 (P=0.003). Prompted by this data, we evaluated the novel parthenolide analog, LC-1, in 54 CLL patient samples. LC-1 induced apoptosis in all the samples tested with a mean LD50 of 2.8µM after 24h; normal B- and T-cells were significantly more resistant to its apoptotic effects (P<0.0001). Apoptosis was preceded by a marked loss of NF-B DNA-binding and sensitivity to LC-1 correlated with basal Rel A DNA binding (P=0.03, r2=0.15). Furthermore, Rel A DNA binding but was inversely correlated with sensitivity to fludarabine (P=0.001, r2=0.3) implicating Rel A in fludarabine resistance. Taken together, these data indicate that Rel A represents an excellent therapeutic target for this incurable disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CLL and activated NF-B: living partnership Erin Hertlein and John C. Byrd Blood 2008 111: 4427. [Full Text] [PDF]

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