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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-05-1600.
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.
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