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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 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 Citation Map 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 HighWire 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 Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The NF-B subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target Saman Hewamana1,2, Suhair Alghazal1, Thet Thet Lin1, Matthew Clement2, Chris Jenkins1, Monica L. Guzman3, Craig T. Jordan3, Sundar Neelakantan4, Peter A. Crooks4, Alan K. Burnett1, Guy Pratt5, Chris Fegan1, Clare Rowntree1, Paul Brennan2, and Chris Pepper1 Departments of1 Haematology and 2 Medical Biochemistry & Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom; 3 Division of Hematology/Oncology, University of Rochester School of Medicine, Rochester, NY; 4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington; and 5 Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom In this study, we characterized nuclear factor B (NF-B) subunit DNA binding in chronic lymphocytic leukemia (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 = .01) with high white cell count (P = .01) and shorter lymphocyte doubling time (P = .01). NF-B induction after in vitro stimulation with anti-IgM was associated with increased in vitro survival (P < .001) and expression of the signaling molecule ZAP-70 (P = .003). Prompted by these 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 2.8 µM after 24 hours; normal B and T cells were significantly more resistant to its apoptotic effects (P < .001). 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 = .03, r2 = 0.15). Furthermore, Rel A DNA binding was inversely correlated with sensitivity to fludarabine (P = .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] This article has been cited by other articles: T. Enzler, A. P. Kater, W. Zhang, G. F. Widhopf II, H.-Y. Chuang, J. Lee, E. Avery, C. M. Croce, M. Karin, and T. J. Kipps Chronic lymphocytic leukemia of E{micro}-TCL1 transgenic mice undergoes rapid cell turnover that can be offset by extrinsic CD257 to accelerate disease progression Blood, November 12, 2009; 114(20): 4469 - 4476. [Abstract] [Full Text] [PDF] S.-S. Chen, A. Raval, A. J. Johnson, E. Hertlein, T.-H. Liu, V. X. Jin, M. H. Sherman, S.-J. Liu, D. W. Dawson, K. E. Williams, et al. Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia PNAS, August 11, 2009; 106(32): 13433 - 13438. [Abstract] [Full Text] [PDF] M. Lopez-Guerra, G. Roue, P. Perez-Galan, R. Alonso, N. Villamor, E. Montserrat, E. Campo, and D. Colomer p65 Activity and ZAP-70 Status Predict the Sensitivity of Chronic Lymphocytic Leukemia Cells to the Selective I{kappa}B Kinase Inhibitor BMS-345541 Clin. Cancer Res., April 15, 2009; 15(8): 2767 - 2776. [Abstract] [Full Text] [PDF] S. Hewamana, T. T. Lin, C. Rowntree, K. Karunanithi, G. Pratt, R. Hills, C. Fegan, P. Brennan, and C. Pepper Rel A Is an Independent Biomarker of Clinical Outcome in Chronic Lymphocytic Leukemia J. Clin. Oncol., February 10, 2009; 27(5): 763 - 769. [Abstract] [Full Text] [PDF] S. Hewamana, T. T. Lin, C. Jenkins, A. K. Burnett, C. T. Jordan, C. Fegan, P. Brennan, C. Rowntree, and C. Pepper The Novel Nuclear Factor-{kappa}B Inhibitor LC-1 Is Equipotent in Poor Prognostic Subsets of Chronic Lymphocytic Leukemia and Shows Strong Synergy with Fludarabine Clin. Cancer Res., December 15, 2008; 14(24): 8102 - 8111. [Abstract] [Full Text] [PDF]

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