SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-05-1600. This Article Full Text (PDF) All Versions of this Article: 2002-05-1600v1 101/4/1270    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 Stam, R. W Articles by Pieters, R. Search for Related Content PubMed PubMed Citation Articles by Stam, R. W Articles by Pieters, R. Social Bookmarking                   What's this? Submitted May 30, 2002 Accepted October 1, 2002 Differential mRNA expression of Ara-C metabolizing enzymes explains Ara-C sensitivity in MLL gene rearranged infant Acute Lymphoblastic Leukemia (ALL) Ronald W Stam*, Monique L den Boer, Jules P P Meijerink, Marli E G Ebus, Godefridus J Peters, Paul Noordhuis, Gritta E Janka-Schaub, Scott A Armstrong, Stanley J Korsmeyer, and Rob Pieters Divison of Oncology / Hematology, Erasmus MC / Sophia Children's Hospital, Rotterdam, The Netherlands Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands Department of Pediatric Hematology/Oncology, University Hospital Eppendorf, Hamburg, Germany Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pediatric Hematology/Oncology, Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA, USA * Corresponding author; email: stam{at}kgk.fgg.eur.nl. Infant ALL is characterized by a high incidence of MLL gene rearrangements, a poor outcome and resistance to chemotherapeutic drugs. One exception is Ara-C, to which infant ALL cells are highly sensitive. To investigate the mechanism underlying Ara-C sensitivity in infants with ALL, mRNA levels of Ara-C metabolizing enzymes were measured in infants (n=18) and non-infants with ALL (n=24). In the present study, infant ALL cells were 3.3-fold more sensitive to Ara-C (p=0.007) and accumulated 2.3-fold more Ara-CTP (p=0.011) upon exposure to Ara-C, compared to older children with ALL. Real-time quantitative RT-PCR (TaqMan) revealed that infants express 2-fold less of the Ara-C phosphorylating enzyme deoxycytidine kinase (dCK) mRNA (p=0.026) but 2.5-fold more mRNA of the equilibrative nucleoside transporter 1 (hENT1), responsible for Ara-C membrane transport (p=0.001). The mRNA expression of pyrimidine nucleotidase I (PN-I), cytidine deaminase (CDA) and deoxycytidylate deaminase (dCMPD) did not differ significantly between both groups. hENT1 mRNA expression inversely correlated with in vitro resistance to Ara-C (rs=-0.58, p=0.006). The same differences concerning dCK and hENT1 mRNA expression were observed between MLL gene rearranged (n=14) and germline MLL cases (n=25). An oligonucleotide microarray screen (Affymetrix) comparing MLL gene rearranged ALL with non-rearranged ALL patients, also showed a 1.9-fold lower dCK (p=0.001) and a 2.7-fold higher hENT1 (p=0.046) mRNA expression in MLL gene rearranged ALL patients. We conclude that an elevated expression of hENT1, which transports Ara-C across the cell membrane, contributes to Ara-C sensitivity in MLL gene rearranged infant ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. W. Stam, M. L. Den Boer, P. Schneider, J. de Boer, J. Hagelstein, M. G. Valsecchi, P. de Lorenzo, S. E. Sallan, H. J. M. Brady, S. A. Armstrong, et al. Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL-rearranged infant acute lymphoblastic leukemia Blood, February 4, 2010; 115(5): 1018 - 1025. [Abstract] [Full Text] [PDF] M. Liedtke and M. L. Cleary Therapeutic targeting of MLL Blood, June 11, 2009; 113(24): 6061 - 6068. [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] J. M. de Bont, J. M. Kros, M. M.C.J. Passier, R. E. Reddingius, P. A.E. S. Smitt, T. M. Luider, M. L. d. Boer, and R. Pieters Differential expression and prognostic significance of SOX genes in pediatric medulloblastoma and ependymoma identified by microarray analysis Neuro Oncology, October 1, 2008; 10(5): 648 - 660. [Abstract] [Full Text] [PDF] J. Cai, V. L. Damaraju, N. Groulx, D. Mowles, Y. Peng, M. J. Robins, C. E. Cass, and P. Gros Two Distinct Molecular Mechanisms Underlying Cytarabine Resistance in Human Leukemic Cells Cancer Res., April 1, 2008; 68(7): 2349 - 2357. [Abstract] [Full Text] [PDF] W. J. E. Tissing, M. L. den Boer, J. P. P. Meijerink, R. X. Menezes, S. Swagemakers, P. J. van der Spek, S. E. Sallan, S. A. Armstrong, and R. Pieters Genomewide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells Blood, May 1, 2007; 109(9): 3929 - 3935. [Abstract] [Full Text] [PDF] P. Van Vlierberghe, M. van Grotel, H. B. Beverloo, C. Lee, T. Helgason, J. Buijs-Gladdines, M. Passier, E. R. van Wering, A. J. P. Veerman, W. A. Kamps, et al. The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia Blood, November 15, 2006; 108(10): 3520 - 3529. [Abstract] [Full Text] [PDF] A. Holleman, M. L. den Boer, M. H. Cheok, K. M. Kazemier, D. Pei, J. R. Downing, G. E. Janka-Schaub, U. Gobel, U. B. Graubner, C.-H. Pui, et al. Expression of the outcome predictor in acute leukemia 1 (OPAL1) gene is not an independent prognostic factor in patients treated according to COALL or St Jude protocols Blood, September 15, 2006; 108(6): 1984 - 1990. [Abstract] [Full Text] [PDF] W. J. E. Tissing, J. P. P. Meijerink, B. Brinkhof, M. J. C. Broekhuis, R. X. Menezes, M. L. den Boer, and R. Pieters Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALL Blood, August 1, 2006; 108(3): 1045 - 1049. [Abstract] [Full Text] [PDF] S. D. Gore, S. Baylin, E. Sugar, H. Carraway, C. B. Miller, M. Carducci, M. Grever, O. Galm, T. Dauses, J. E. Karp, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res., June 15, 2006; 66(12): 6361 - 6369. [Abstract] [Full Text] [PDF] D. K. Vanaja, K. V. Ballman, B. W. Morlan, J. C. Cheville, R. M. Neumann, M. M. Lieber, D. J. Tindall, and C. Y.F. Young PDLIM4 Repression by Hypermethylation as a Potential Biomarker for Prostate Cancer Clin. Cancer Res., February 15, 2006; 12(4): 1128 - 1136. [Abstract] [Full Text] [PDF] A. Holleman, M. L. den Boer, R. X. de Menezes, M. H. Cheok, C. Cheng, K. M. Kazemier, G. E. Janka-Schaub, U. Gobel, U. B. Graubner, W. E. Evans, et al. The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia Blood, January 15, 2006; 107(2): 769 - 776. [Abstract] [Full Text] [PDF] R. W. Stam, M. L. den Boer, P. Schneider, P. Nollau, M. Horstmann, H. B. Beverloo, E. van der Voort, M. G. Valsecchi, P. de Lorenzo, S. E. Sallan, et al. Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia Blood, October 1, 2005; 106(7): 2484 - 2490. [Abstract] [Full Text] [PDF] A. Holleman, M. L. d. Boer, K. M. Kazemier, H. B. Beverloo, A. R. M. von Bergh, G. E. Janka-Schaub, and R. Pieters Decreased PARP and procaspase-2 protein levels are associated with cellular drug resistance in childhood acute lymphoblastic leukemia Blood, September 1, 2005; 106(5): 1817 - 1823. [Abstract] [Full Text] [PDF] M. Michael and M.M. Doherty Tumoral Drug Metabolism: Overview and Its Implications for Cancer Therapy J. Clin. Oncol., January 1, 2005; 23(1): 205 - 229. [Abstract] [Full Text] [PDF] A. Holleman, M. H. Cheok, M. L. den Boer, W. Yang, A. J.P. Veerman, K. M. Kazemier, D. Pei, C. Cheng, C.-H. Pui, M. V. Relling, et al. Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment N. Engl. J. Med., August 5, 2004; 351(6): 533 - 542. [Abstract] [Full Text] [PDF] C.-H. Pui, M. V. Relling, and J. R. Downing Acute Lymphoblastic Leukemia N. Engl. J. Med., April 8, 2004; 350(15): 1535 - 1548. [Full Text] [PDF] D. G. Gilliland, C. T. Jordan, and C. A. Felix The Molecular Basis of Leukemia Hematology, January 1, 2004; 2004(1): 80 - 97. [Abstract] [Full Text] [PDF] G. Cimino, L. Elia, M. Mancini, L. Annino, B. Anaclerico, P. Fazi, A. Vitale, G. Specchia, F. Di Raimondo, A. Recchia, et al. Clinico-biologic features and treatment outcome of adult pro-B-ALL patients enrolled in the GIMEMA 0496 study: absence of the ALL1/AF4 and of the BCR/ABL fusion genes correlates with a significantly better clinical outcome Blood, September 15, 2003; 102(6): 2014 - 2020. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020