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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 19, 2004 Accepted August 1, 2004 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 Dabbaugh, Darryl Glubrecht, Lawrence D Jewell, Raymond Lai, Thack Lang, James D Young, Helene Merle-Beral, Jacques L Binet, Carol E Cass, and Charles Dumontet Department of Oncology, University of Alberta, Edmonton, Alberta, Canada; Cross Cancer Institute, Edmonton, Alberta, Canada Unite INSERM 590, Centre Leon Berard, Lyon, France Hotel Dieu, Paris, France Cross Cancer Institute, Edmonton, Alberta, Canada Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada Hopital de la Pitie Salpetriere, Paris, France Unite INSERM 590, Centre Leon Berard, Lyon, France; Hopital Edouard Herriot, Lyon, France * Corresponding author; email: johnmack{at}cancerboard.ab.ca. Resistance to fludarabine is observed in 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 RT-PCR was performed on sample RNA to determine the relative levels of mRNA of three 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 three 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 two distinct populations of CLL. Cluster 2 patients experienced a 3.4-fold higher risk of disease progression than cluster 1 patients (p=0.0058, Logrank analysis). Furthermore, independent analysis of the individual genes of interest revealed statistically significant differences for risk of disease progression (adjusted hazard ratios) with under-expression of dNT-1 (HR=0.45 p=0.042), CD73 (HR=0.40, p=0.022), dCK (HR=0.0.48, p=0.035), and over-expression of hCNT3 (HR=4.7, p=0.0007) genes. Subjects with elevated hCNT3 expression experienced a lower complete response rate to fludarabine therapy (11% vs 69%, p =0.002). 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: K. D. Ibarra and J. K. Pfeiffer Reduced Ribavirin Antiviral Efficacy via Nucleoside Transporter-Mediated Drug Resistance J. Virol., May 1, 2009; 83(9): 4538 - 4547. [Abstract] [Full Text] [PDF] 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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