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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1393-1400
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
Jeffrey W. Taub,
Xi Huang,
Larry H. Matherly,
Mark L. Stout,
Steven A. Buck,
Gita V. Massey,
David L. Becton,
Myron N. Chang,
Howard
J. Weinstein, and
Yaddanapudi Ravindranath
From the Division of Pediatric Hematology/Oncology, Children's
Hospital of Michigan, Detroit, MI; the Experimental and Clinical
Therapeutics Program, Barbara Ann Karmanos Cancer Institute,
Departments of Pediatrics and Pharmacology, Wayne State University
School of Medicine, Detroit, MI; the Medical College of Virginia,
Richmond, VA; the University of Arkansas, Little Rock, AR; the
University of Florida, Gainesville, FL; the Department of Pediatrics,
Massachusetts General Hospital, Boston, MA; and the Pediatric Oncology
Group, Chicago, IL.
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- -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-bromide (MTT)
assay (P = .003) and the generation of 3H-ara-C
triphosphate (ara-CTP) after in vitro incubations with 5 µmol/L
3H-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.
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