Enhanced metabolism of 1-β-D-arabinofuranosylcytosine in Down syndrome cells: A contributing factor to the superior event free survival of down syndrome children with acute myeloid leukemia

Abstract

Down syndrome (DS) children with acute myeloid leukemia (AML) have significantly higher event-free survival (EFS) rates compared with non-DS children when treated with protocols containing 1-β-D- arabinofuranosylcytosine (araC). Sensitivity and metabolism of era-C was examined in myeloblasts from DS and non-DS patients with AML, DS infants with the transient myeloproliferative disorder, and Epstein-Barr Virus (EBV) transformed lymphoblastoid cell lines with and without trisomy 21. DS myeloblasts were approximately 10-fold more sensitive to ara-C (measured by the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) colorimetric sensitivity assay), compared with non-DS myeloblasts, following exposure to ara-C for 72 hours. Mean levels of 1-β-D- arabinofuranosylcytosine 5'-triphosphate (ara-CTP) were significantly higher in DS myeloblasts compared with non-DS myeloblasts after incubation with 5 μmol/L ara-C (621.4 v 228.4 pmol/mg protein). DS cell lines also generated higher levels of ara-CTP compared with cell lines with diploid chromosome numbers (66.5 v 13.6 pmol/mg protein and 137.6 v 41.7 pmol/mg protein at 1 and 5 μmol/L ara-C, respectively). Elevated era-CTP levels in the DS cells were accompanied by slightly lower levels of endogenous deoxycytidine triphosphate (dCTP) pools, slightly greater extent of ara-C incorporation into DNA, and increased relative numbers of double strand DNA strand breaks. There were no significant differences in the cell cycle distributions of DS and non-DS cells. These in vitro studies support our hypothesis that enhanced metabolism of ara-C in DS cells may be a contributing factor to the superior survival rate of DS children with AML and is possibly based on a gene dosage effect of genes localized to chromosome 21 including cystathionine-β- synthase. Further study of the mechanisms (ie, alterations in dCTP pools and DNA methylation) involved may lead to improvements in the treatment of all AML patients.

Publication Title

Blood

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