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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3807-3817. Prepublished online as a Blood First Edition Paper on July 3, 2008; DOI 10.1182/blood-2008-05-157131. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-05-157131v1 112/9/3807    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 Pepper, C. Articles by Fegan, C. Search for Related Content PubMed PubMed Citation Articles by Pepper, C. Articles by Fegan, C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 14, 2008 Accepted June 28, 2008 Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers Chris Pepper*, Thet Thet Lin, Guy Pratt, Saman Hewamana, Paul Brennan, Louise Hiller, Robert Hills, Rachel Ward, Jane Starczynski, Belinda Austen, Laura Hooper, Tatjana Stankovic, and Chris Fegan Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom Haematology, Heartlands and Solihull NHS Trust, Birmingham, United Kingdom Medical Biochemistry & Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom Warwick Medical School Clinical Trials Unit, Warwick University, Coventry, United Kingdom Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom * Corresponding author; email: peppercj{at}cf.ac.uk. Bcl-2 family proteins play a critical role in the regulation of apoptosis in chronic lymphocytic leukemia (CLL). However, their association with established prognostic markers is unknown. In this study we analysed the expression of Bcl-2, Bax and Mcl-1 in 185 CLL patients and evaluated their relationship with other prognostic markers, in vitro sensitivity to fludarabine and clinical outcome. Mcl-1 expression was significantly correlated with stage of disease (P<0.0001), lymphocyte doubling time (P=0.01), VH gene mutation status (P<0.0001) CD38 expression (P<0.0001) and ZAP-70 expression (P=0.003). In addition, Mcl-1 and Mcl-1/Bax ratios showed strong correlations with in vitro resistance to fludarabine (P=0.005 and P<0.0001 respectively). Furthermore, elevated Mcl-1 expression and Mcl-1/Bax ratios were predictive of time to first treatment in the whole cohort (P<0.0001 and P<0.0001 respectively) and in stage A patients only (P=0.002 and P=0.0003 respectively). Taken together, our data show that Mcl-1 is a key controller of in vitro drug resistance and is an important regulator of disease progression and outcome in CLL. It therefore represents a promising therapeutic target in this incurable condition. The close correlation between Mcl-1 expression and VH gene mutation status, CD38 expression and ZAP-70 expression offers a biological explanation for their association with adverse prognosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Mcl-1: the 1 in CLL Varsha Gandhi, Kumudha Balakrishnan, and Lisa S. Chen Blood 2008 112: 3538-3540. [Full Text] [PDF] This article has been cited by other articles: T. D. Shanafelt, T. G. Call, C. S. Zent, B. LaPlant, D. A. Bowen, M. Roos, C. R. Secreto, A. K. Ghosh, B. F. Kabat, M.-J. Lee, et al. Phase I Trial of Daily Oral Polyphenon E in Patients With Asymptomatic Rai Stage 0 to II Chronic Lymphocytic Leukemia J. Clin. Oncol., August 10, 2009; 27(23): 3808 - 3814. [Abstract] [Full Text] [PDF] B. Stamatopoulos, N. Meuleman, B. Haibe-Kains, P. Saussoy, E. Van Den Neste, L. Michaux, P. Heimann, P. Martiat, D. Bron, and L. Lagneaux microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification Blood, May 21, 2009; 113(21): 5237 - 5245. [Abstract] [Full Text] [PDF] D. M. Lucas, R. B. Edwards, G. Lozanski, D. A. West, J. D. Shin, M. A. Vargo, M. E. Davis, D. M. Rozewski, A. J. Johnson, B.-N. Su, et al. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo Blood, May 7, 2009; 113(19): 4656 - 4666. [Abstract] [Full Text] [PDF] R. Chen, W. G. Wierda, S. Chubb, R. E. Hawtin, J. A. Fox, M. J. Keating, V. Gandhi, and W. Plunkett Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia Blood, May 7, 2009; 113(19): 4637 - 4645. [Abstract] [Full Text] [PDF] F. T. Awan, N. E. Kay, M. E. Davis, W. Wu, S. M. Geyer, N. Leung, D. F. Jelinek, R. C. Tschumper, C. R. Secreto, T. S. Lin, et al. Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab Blood, January 15, 2009; 113(3): 535 - 537. [Abstract] [Full Text] [PDF] K. Balakrishnan, J. A. Burger, W. G. Wierda, and V. Gandhi AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance Blood, January 1, 2009; 113(1): 149 - 153. [Abstract] [Full Text] [PDF]

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