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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4296-4307
Hypomethylation Status of CpG Sites at the Promoter Region and
Overexpression of the Human MDR1 Gene in Acute Myeloid
Leukemias
Masaharu Nakayama,
Morimasa Wada,
Taishi Harada,
Jun Nagayama,
Hitoshi Kusaba,
Koichi Ohshima,
Mitsuo Kozuru,
Hirokazu Komatsu,
Ryuzo Ueda, and
Michihiko Kuwano
From the Department of Biochemistry, Kyushu University School of
Medicine, Fukuoka, Japan; First Department of Pathology, Fukuoka
University School of Medicine, Fukuoka, Japan; National Kyushu Cancer
Center, Fukuoka, Japan; and Second Department of Internal Medicine,
Nagoya City University School of Medicine, Nagoya, Japan.
Selection of human cells for resistance to vincristine or
doxorubicin often induces overexpression of the multidrug resistance 1 gene (MDR1), which encodes the cell surface P-glycoprotein, as
a result of gene amplification or transcriptional activation. Moreover,
overexpression of the MDR1 gene has been shown to be associated
closely with clinical outcome in various hematological malignancies,
including acute myeloid leukemia (AML). However, the precise mechanism
underlying overexpression of the MDR1 gene during acquisition
of drug resistance remains unclear. We recently described an inverse
correlation between the methylation status of CpG sites at the promoter
region and expression of the MDR1 gene in malignant cell lines.
In this study, we expanded this analysis to 42 clinical AML samples. We
adapted a quantitative reverse transcription-polymerase chain reaction
(RT-PCR) assay for gene expression and a quantitative PCR after
digestion by Hpa II for methylation status of the MDR1
gene. We observed a statistically significant inverse correlation
between methylation and MDR1 expression in clinical samples.
The hypomethylation status of the MDR1 promoter region might be
a necessary condition for MDR1 gene overexpression and
establishment of P-glycoprotein-mediated multidrug
resistance in AML patients.
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