Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies
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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.
We thank S Mellen and L Messler for expert technical assistance. This work was supported by NIH Grants CA84986 and P50 CA96888 and a grant from the Rheinisch-Westfaelische Technische
Hochschule Aachen.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St, Baltimore, 21231, MD, USA
Oliver Galm, Hiromu Suzuki, Yoshimitsu Akiyama, Manel Esteller, Malcolm V Brock, Stephen B Baylin & James G Herman
Medizinische Klinik IV, Universitaetsklinikum Aachen, Aachen, 52074, Germany
Cancer Epigenetics Laboratory, Spanish National Cancer Centre, Madrid, 28029, Spain
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