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, Rob Pieters

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168 Citations (Scopus)

Abstract

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 (r(s) = -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.

Original languageEnglish
Pages (from-to)1270-6
Number of pages7
JournalBlood
Volume101
Issue number4
DOIs
Publication statusPublished - 15 Feb 2003
Externally publishedYes

Keywords

  • Arabinofuranosylcytosine Triphosphate/metabolism
  • Cell Survival
  • Child
  • Child, Preschool
  • Cytarabine/metabolism
  • DCMP Deaminase/genetics
  • DNA-Binding Proteins/genetics
  • Deoxycytidine Kinase/genetics
  • Drug Resistance, Neoplasm/genetics
  • Equilibrative Nucleoside Transporter 1/genetics
  • Female
  • Gene Expression
  • Gene Rearrangement
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Infant
  • Male
  • Myeloid-Lymphoid Leukemia Protein
  • Oligonucleotide Array Sequence Analysis
  • Polymerase Chain Reaction
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
  • Proto-Oncogenes
  • Pyrimidine Nucleotides/genetics
  • RNA, Messenger/analysis
  • Transcription Factors
  • Tumor Cells, Cultured

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