Expression of chromosome 21-localized genes in acute myeloid leukemia: Differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin

The high event-free survival rates of Down syndrome (DS) children with acut e myeloid leukemia (AML) are due, in part, to increased in vitro sensitivit y of DS myeloblasts to cytosine arabinoside (ara-C) and daunorubicin and th e greater generation of ara-C triphosphate (ara-CTP) from ara-C compared wi th myeloblasts from non DS patients (Taub et at, Blood 87:3395, 1996). This study further explores the molecular basis of chemotherapy sensitivity of DS AML patients by examining the expression of chromosome 21-localized gene s in myeloblasts from newly diagnosed AML patients. Transcript levels of tw o chromosome 21-localized genes, cystathionine-P-synthase (CBS) and superox ide dismutase (SOD), measured by quantitative reverse transcriptase-polymer ase chain reaction (RT-PCR), were 12.0- and 3.8-fold higher in DS compared with non-DS myeloblasts (P < .0001 and P < .0001, respectively). Conversely , there were no significant increases in transcripts for 2 other chromosome 21-localized genes, carbonyl reductase and the reduced folate carrier. CBS transcript levels correlated with both in vitro ara-C sensitivity measured by the 3-[4,5-dimethyl-thiazol-2-yl]-2.5-diphenyltetrazolium-bromide [MTT) assay (P = .003) and the generation of H-3-ara-C triphosphate (ara-CTP) af ter in vitro incubations with 5 mu mol/L H-3-ara-C (P = .0003). Transcripts of deoxycytidine kinase were 2.6-fold higher in DS compared with non-DS ce lls and may be a factor in the enhanced metabolism of ara-C in DS cells. Th ere was no significant correlation of SOD transcripts with in vitro ara-C a nd daunorubicin sensitivities. Increased CBS transcripts could result in el evated CBS activity, which modulates ara-C metabolism by altering reduced f olate pools, deoxycytidine triphosphate pools, S-adenosylmethionine levels, and/or methylation of the deoxycytidine kinase gene. The further identific ation of the molecular mechanisms of chemotherapy sensitivity of DS AML pat ients may lead to significant improvements in the treatment and cure of AML . (C) 1999 by The American Society of Hematology.