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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2790-2796. Prepublished online as a Blood First Edition Paper on December 26, 2007; DOI 10.1182/blood-2007-10-110460. This Article Full Text (PDF) All Versions of this Article: blood-2007-10-110460v1 111/5/2790    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Agrawal, S. G Articles by Jia, L. Search for Related Content PubMed PubMed Citation Articles by Agrawal, S. G Articles by Jia, L. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 11, 2007 Accepted November 23, 2007 Increased proteasomal degradation of Bax is a common feature of poor prognosis chronic lymphocytic leukemia Samir G Agrawal*, Feng-Ting Liu, Catherine Wiseman, Sima Shirali, Hongxiang Liu, Debra Lillington, Ming-Qing Du, Denise Syndercombe-Court, Adrian C. Newland, John G Gribben, and Li Jia Centre for Haematology, Institute of Cell and Molecular Science, CRUK, Queen Mary University of London and Barts and the London NHS Trust, London, United Kingdom Department of Haematology, CRUK, Queen Mary University of London and Barts and the London NHS Trust, London, United Kingdom Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom Department of Cytogenetics, CRUK, Queen Mary University of London and Barts and the London NHS Trust, London, United Kingdom Department of Haemato-Oncology, and Institute of Cancer, CRUK, Queen Mary University of London and Barts and the London NHS Trust, London, United Kingdom * Corresponding author; email: s.g.agrawal{at}qmul.ac.uk. Many biological markers are associated with poor prognosis in chronic lymphocytic leukemia (CLL), but their mechanistic role remains unclear. Bax is an essential pro-apoptotic protein and decreased levels in malignant cells lead to resistance to apoptosis. Using a Bax degradation activity (BDA) assay, CLL cells were found to show variable Bax instability. However, BDA did not correlate with Bax protein levels: BDA positive and negative cases had high and low baseline Bax levels. BDA positive cases showed a marked accumulation of poor prognostic markers-unmutated immunoglobulin heavy chain variable genes, ZAP-70/CD38 positivity, 11q22/17p13 deletion, and short lymphocyte doubling time. Patients with BDA positive cells had a shorter median overall survival (OS) (126 months v. not reached, p = 0.011) and time to first treatment (16 v. 156 months, p = 0.029) than BDA negative cases. Dual BDA and ZAP-70 positivity had a median OS of 84 months (p = 0.012). The BDA assay measures the intrinsic ubiquitin/proteasome activity of CLL cells and dynamic changes in Bax protein levels over time. Mechanistically, Bax instability may represent a final common pathway for disparate prognostic markers, as well as being itself an indicator of poor prognosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Proto-Siqueira, R. A. Panepucci, F. P. Careta, A. Lee, A. Clear, K. Morris, C. Owen, E. G. Rizzatti, W. A. Silva Jr, R. P. Falcao, et al. SAGE analysis demonstrates increased expression of TOSO contributing to Fas-mediated resistance in CLL Blood, July 15, 2008; 112(2): 394 - 397. [Abstract] [Full Text] [PDF]

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