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Blood, 15 January 2005, Vol. 105, No. 2, pp. 767-774. Prepublished online as a Blood First Edition Paper on September 28, 2004; DOI 10.1182/blood-2004-03-1046. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-03-1046v1 105/2/767    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 Mackey, J. R. Articles by Dumontet, C. Search for Related Content PubMed PubMed Citation Articles by Mackey, J. R. Articles by Dumontet, C. Related Collections Neoplasia Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Quantitative analysis of nucleoside transporter and metabolism gene expression in chronic lymphocytic leukemia (CLL): identification of fludarabine-sensitive and -insensitive populations John R. Mackey, Carlos M. Galmarini, Kathryn A. Graham, Anil A. Joy, Alain Delmer, Laith Dabbagh, Darryl Glubrecht, Lawrence D. Jewell, Raymond Lai, Thack Lang, John Hanson, James D. Young, Helene Merle-Béral, Jacques L. Binet, Carol E. Cass, and Charles Dumontet From the Departments of Oncology, Laboratory Medicine and Pathology, and Physiology, University of Alberta, Alberta, Canada; Cross Cancer Institute, Edmonton, Alberta, Canada; Unité INSERM 590, Centre Leon Bérard, Lyon, France; Hotel Dieu, Paris, France; Hôpital de la Pitié Salpétrière, Paris, France; and University Claude Bernard, Lyon, France. Resistance to fludarabine is observed in the clinic, and molecular predictive assays for benefit from chemotherapy are required. Our objective was to determine if expression of nucleoside transport and metabolism genes was associated with response to fludarabine therapy in patients with chronic lymphocytic leukemia (CLL). CLL cells from 56 patients were collected prior to treatment with fludarabine. Quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) was performed on sample RNA to determine the relative levels of mRNA of 3 nucleoside transporters that mediate fludarabine uptake (human equilibrative nucleoside transporter 1 [hENT1], human equilibrative nucleoside transporter 2 [hENT2], and human concentrative nucleoside transporter 3 [hCNT3]), deoxycytidine kinase (dCK), and 3 5'-nucleotidases (ecto-5'nucleotidase [CD73], deoxynucleotidase-1 [dNT-1], and cytoplasmic high-Km 5-nucleotidase [CN-II]). Two-dimensional hierarchical cluster analysis of gene expression identified 2 distinct populations of CLL. Cluster 2 patients experienced a 3.4-fold higher risk of disease progression than cluster 1 patients (P = .0058, log-rank analysis). Furthermore, independent analysis of the individual genes of interest revealed statistically significant differences for risk of disease progression (adjusted hazard ratios [HRs]) with underexpression of dNT-1 (HR = 0.45; P = .042), CD73 (HR = 0.40; P = .022), and dCK (HR = 0.0.48; P = .035), and overexpression of hCNT3 (HR = 4.7; P = .0007) genes. Subjects with elevated hCNT3 expression experienced a lower complete response rate to fludarabine therapy (11% vs 69%; P = .002). No hCNT3-mediated plasma membrane nucleoside transport was detected in CLL samples expressing hCNT3 message, and hCNT3 protein was localized to the cytoplasm with immunohistochemical and confocal microscopy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Errasti-Murugarren, M. Molina-Arcas, F. J. Casado, and M. Pastor-Anglada A splice variant of the SLC28A3 gene encodes a novel human concentrative nucleoside transporter-3 (hCNT3) protein localized in the endoplasmic reticulum FASEB J, January 1, 2009; 23(1): 172 - 182. [Abstract] [Full Text] [PDF] M. Lopez-Guerra, L. Trigueros-Motos, M. Molina-Arcas, N. Villamor, F. J. Casado, E. Montserrat, E. Campo, D. Colomer, and M. Pastor-Anglada Identification of TIGAR in the equilibrative nucleoside transporter 2-mediated response to fludarabine in chronic lymphocytic leukemia cells Haematologica, December 1, 2008; 93(12): 1843 - 1851. [Abstract] [Full Text] [PDF] V. L. Damaraju, A. N. Elwi, C. Hunter, P. Carpenter, C. Santos, G. M. Barron, X. Sun, S. A. Baldwin, J. D. Young, J. R. Mackey, et al. Localization of broadly selective equilibrative and concentrative nucleoside transporters, hENT1 and hCNT3, in human kidney Am J Physiol Renal Physiol, July 1, 2007; 293(1): F200 - F211. [Abstract] [Full Text] [PDF]

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