Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies.
The tissue inhibitor of metalloproteinases-2 (TIMP-2) is known to antagonize matrix metalloproteinase activity and to suppress tumor growth, angiogenesis, invasion and metastasis. We analysed the methylation status of the CpG island in the TIMP-2 promoter region by methylation-specific polymerase chain reaction (MSP) in hematopoietic cell lines. TIMP-2 promoter hypermethylation in the lymphoma cell line Raji and the leukemia cell line KG1a was associated with transcriptional repression. Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in TIMP-2 upregulation in both cell lines. TIMP-2 was expressed in the cell lines HL60, U266 and XG1, which carry an unmethylated promoter region. MSP analysis of primary patient samples revealed aberrant methylation of TIMP-2 in 33/90 (36.7%) cases of non-Hodgkin's lymphoma (NHL), but not in normal peripheral blood lymphocytes as well as in nonmalignant bone marrow and lymph nodes. The frequency of TIMP-2 methylation was slightly higher in aggressive NHL subtypes compared to those with an indolent subtype (38.6 versus 33.3%). In contrast, TIMP-2 was not hypermethylated in any of the 40 cases of acute myelogenous leukemia examined. We conclude that promoter hypermethylation of TIMP-2 is a novel epigenetic event in the pathogenesis of lymphoid malignancies and may contribute to a more aggressive NHL phenotype.
Galm
Oliver
O
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St, Baltimore, MD 21231, USA.
Suzuki
Hiromu
H
Akiyama
Yoshimitsu
Y
Esteller
Manel
M
Brock
Malcolm V
MV
Osieka
Rainhardt
R
Baylin
Stephen B
SB
Herman
James G
JG
D045744:Cell Line, Tumor; D019175:DNA Methylation; D004789:Enzyme Activation; D006410:Hematopoiesis; D006801:Humans; D007150:Immunohistochemistry; D008223:Lymphoma / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*
D019716:Tissue Inhibitor of Metalloproteinase-2