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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 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 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 Pepper, C. Articles by Fegan, C. Search for Related Content PubMed PubMed Citation Articles by Pepper, C. Articles by Fegan, C. Related Collections Neoplasia Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers Chris Pepper1, Thet Thet Lin1, Guy Pratt2,3, Saman Hewamana1,4, Paul Brennan4, Louise Hiller5, Robert Hills1, Rachel Ward1, Jane Starczynski2, Belinda Austen3, Laura Hooper2, Tatjana Stankovic3, and Chris Fegan1 1 Department of Haematology, School of Medicine, Cardiff University, Cardiff; 2 Department of Haematology, Heartlands and Solihull National Health Service (NHS) Trust, Birmingham; 3 Institute for Cancer Studies, University of Birmingham, Birmingham; 4 Department of Medical Biochemistry & Immunology, School of Medicine, Cardiff University, Cardiff; and 5 Warwick Medical School Clinical Trials Unit, University of Warwick, Coventry, United Kingdom 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 analyzed 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 < .001), lymphocyte doubling time (P = .01), VH gene mutation status (P < .001), CD38 expression (P < .001), and ZAP-70 expression (P = .003). In addition, Mcl-1 and Mcl-1/Bax ratios showed strong correlations with in vitro resistance to fludarabine (P = .005 and P < .001, respectively). Furthermore, elevated Mcl-1 expression and Mcl-1/Bax ratios were predictive of time to first treatment in the whole cohort (P < .001 and P < .001, respectively) and in stage A patients only (P = .002 and P = .001, 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 biologic 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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