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Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies

Oncogene volume 24, pages 4799–4805 (2005)Cite this article

Abstract

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. 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

  2. Medizinische Klinik IV, Universitaetsklinikum Aachen, Aachen, 52074, Germany

    Oliver Galm & Rainhardt Osieka

  3. Cancer Epigenetics Laboratory, Spanish National Cancer Centre, Madrid, 28029, Spain

    Manel Esteller

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  1. Oliver Galm
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Correspondence to James G Herman.

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Galm, O., Suzuki, H., Akiyama, Y. et al. Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies. Oncogene 24, 4799–4805 (2005). https://doi.org/10.1038/sj.onc.1208599

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