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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-05-1600.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1270-1276
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Differential mRNA expression of Ara-C-metabolizing enzymes
explains Ara-C sensitivity in MLL gene-rearranged infant
acute lymphoblastic leukemia
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
From the University Hospital Rotterdam/Sophia
Children's Hospital, Department of Pediatric Oncology/Hematology,
Erasmus Medical Center, Rotterdam, The Netherlands; the
Department of Medical Oncology, Vr e Universiteit University
Medical Center, Amsterdam, The Netherlands; the
Cooperative Acute Lymphoblastic Leukemia (COALL) study group,
Hamburg, Germany; the Department of Pediatric Oncology,
the Department of Cancer Immunology and AIDS, and the Howard Hughes
Medical Institute, Dana-Farber Cancer Institute, Boston, MA; the
Division of Pediatric Hematology/Oncology, Children's Hospital,
Boston, MA; and Harvard Medical School, Boston, MA.
Infant acute lymphoblastic leukemia (ALL) is characterized by a
high incidence of mixed lineage leukemia (MLL) gene
rearrangements, a poor outcome, and resistance to chemotherapeutic
drugs. One exception is cytosine arabinoside (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
older children (noninfants) with ALL (n = 24). In the present
study, infant ALL cells were 3.3-fold more sensitive to Ara-C
(P = .007) and accumulated 2.3-fold more Ara-CTP
(P = .011) upon exposure to Ara-C, compared with older
children with ALL. Real-time quantitative reverse
trancriptase-polymerase chain reaction (RT-PCR) (TaqMan)
revealed that infants express 2-fold less of the Ara-C
phosphorylating enzyme deoxycytidine kinase (dCK) mRNA
(P = .026) but 2.5-fold more mRNA of the equilibrative nucleoside transporter 1 (hENT1), responsible for Ara-C membrane transport (P = .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 = .006). The same differences concerning dCK and hENT1 mRNA expression were observed
between MLL gene-rearranged (n = 14) and germ line
MLL cases (n = 25). An oligonucleotide microarray screen
(Affymetrix) comparing patients with MLL gene-rearranged ALL with those with nonrearranged ALL also showed a 1.9-fold lower dCK (P = .001) and a 2.7-fold higher
hENT1 (P = .046) mRNA expression in patients
with MLL gene-rearranged ALL. 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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