Preferential hypermethylation of the Dickkopf-1 promoter in core-binding factor leukaemia.
The Dickkopf-1 (DKK1) gene product is an extracellular Wnt inhibitor. Hypermethylation of the DKK1 promoter results in transcriptional silencing and may play an important role in cancer development. Here, we investigated hypermethylation of the DKK1 promoter in patients with acute myeloid leukaemia (AML), especially core-binding factor (CBF) leukaemia. The methylation status of DKK1 was analysed using methylation-specific polymerase chain reaction in 47 patients with AML. DKK1 methylation was found in 14 (29.8%) patients, and more frequently in those with CBF leukaemia (6 of 12 patients), than in those with acute promyelocytic leukaemia (APL) (0 of 6 patients) (P = 0.03). In contrast, Wnt inhibitory factor-1 methylation was found in APL (4 of 6 patients) but not in CBF leukaemia (0 of 12 patients) (P = 0.001). Multivariate analyses suggested that DKK1 methylation was a risk factor for poorer overall survival. Sequential analysis using four paired samples obtained at diagnosis and relapse suggested that DKK1 methylation was involved in the progression of leukaemia. Therefore, DKK1 methylation may be involved in leukaemogenesis, especially in CBF leukaemia, and may be a useful prognostic marker in AML.
Department of Haematology/Oncology, Tokai University School of Medicine, Kanagawa, Japan.
Rikio
R
Suzuki
Makoto
M
Onizuka
Minoru
M
Kojima
Masako
M
Shimada
Satomi
S
Fukagawa
Kosuke
K
Tsuboi
Hiroyuki
H
Kobayashi
Ayumi
A
Shintani
Yoshiaki
Y
Ogawa
Hiroshi
H
Kawada
Tomomitsu
T
Hotta
Kiyoshi
K
Ando
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D050660:Core Binding Factors / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D050660:Core Binding Factors; C501126:DKK1 protein, human; D004273:DNA, Neoplasm; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins