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 acute myeloid leukemia (AML) are due, in part, to increased in vitro sensitivity of DS myeloblasts to cytosine arabinoside (ara-C) and daunorubicin and the greater generation of ara-C triphosphate (ara-CTP) from ara-C compared with myeloblasts from non-DS patients (Taub et al, 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 genes in myeloblasts from newly diagnosed AML patients. Transcript levels of two chromosome 21-localized genes, cystathionine-beta-synthase (CBS) and superoxide dismutase (SOD), measured by quantitative reverse transcriptase-polymerase 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-bro mid e (MTT) assay (P =.003) and the generation of (3)H-ara-C triphosphate (ara-CTP) after in vitro incubations with 5 micromol/L (3)H-ara-C (P =.0003). Transcripts of deoxycytidine kinase were 2.6-fold higher in DS compared with non-DS cells and may be a factor in the enhanced metabolism of ara-C in DS cells. There was no significant correlation of SOD transcripts with in vitro ara-C and daunorubicin sensitivities. Increased CBS transcripts could result in elevated CBS activity, which modulates ara-C metabolism by altering reduced folate pools, deoxycytidine triphosphate pools, S-adenosylmethionine levels, and/or methylation of the deoxycytidine kinase gene. The further identification of the molecular mechanisms of chemotherapy sensitivity of DS AML patients may lead to significant improvements in the treatment and cure of AML.
Taub
J W
JW
Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
Huang
X
X
Matherly
L H
LH
Stout
M L
ML
Buck
S A
SA
Massey
G V
GV
Becton
D L
DL
Chang
M N
MN
Weinstein
H J
HJ
Ravindranath
Y
Y
D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21; D003561:Cytarabine / Q000494:pharmacology* / Q000627:therapeutic use; D003630:Daunorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D004314:Down Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003630:Daunorubicin