Death-associated protein kinase 1 (DAPK1), a proapoptotic serine/threonine kinase, is a candidate tumor suppressor gene. We studied the methylation status of the promoter region of the DAPK1 gene and the expression of the DAPK1 protein in 78 bone marrow samples from untreated patients with myelodysplastic syndrome (MDS) by PCR and Western blot analysis. Hypermethylation of DAPK1 was present in 42.3% (33 of 78) of MDS specimens and was significantly correlated with the loss of DAPK1 mRNA and protein expression (p < 0.01). There were no significant differences in methylation frequency among subgroup of MDS. DAPK1 hypermethylation in MDS was associated with the presence of cytogenetic abnormalities in the bone marrow at the time of the initial diagnosis. A higher frequency of DAPK1 hypermethylation was found in the unfavorable cytogenetic risk group (12 of 21 cases; 57.1%) compared to the favorable cytogenetic risk group (5 of 20 cases; 25.0%, p = 0.0368). These findings suggest that suppression of DAPK1 expression by DNA methylation may play a substantial role in the development of MDS.

Keywords:
DAPK1, Hypermethylation, Myelodysplastic syndromes
1.
Kerbauy DB, Deeg HJ: Apoptosis and antiapoptotic mechanisms in the progression of myelodysplastic syndrome. Exp Hematol 2007;35:1739–1746.
2.
Cohen O, Kimchi A: DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer. Cell Death Differ 2001;8:6–15.
3.
Inbal B, Cohen O, Polak-Charcon S, Kopolovic J, Vadai E, Eisenbach L, Kimchi A: DAP kinase links the control of apoptosis to metastasis. Nature 1997;390:180–184.
4.
Deiss LP, Feinstein E, Berissi H, Cohen O, Kimchi A: Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev 1995;9:15–30.
5.
Raveh T, Droguett G, Horwitz MS, DePinho RA, Kimchi A: DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat Cell Biol 2001;3:1–7.
6.
Robertson KD, Wolffe AP: DNA methylation in health and disease. Nat Rev Genet 2000;1:11–19.
7.
Garcia-Manero G, Issa JP: Histone deacetylase inhibitors: a review of their clinical status as antineoplastic agents. Cancer Invest 2005;23:635–642.
8.
Esteller M, Corn PG, Baylin SB, Herman JG: A gene hypermethylation profile of human cancer. Cancer Res 2001;61:3225–3229.
9.
Katzenellenbogen RA, Baylin SB, Herman JG: Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 1999;93:4347–4353.
10.
Ng MH, To KW, Lo KW, Chan S, Tsang KS, Cheng SH, Ng HK: Frequent death-associated protein kinase promoter hypermethylation in multiple myeloma. Clin Cancer Res 2001;7:1724–1729.
11.
Nakatsuka S, Takakuwa T, Tomita Y, Hoshida Y, Nishiu M, Yamaguchi M, Nishii K, Yang WI, Aozasa K: Hypermethylation of death-associated protein (DAP) kinase CpG island is frequent not only in B-cell but also in T- and natural killer (NK)/T-cell malignancies. Cancer Sci 2003;94:87–91.
12.
Voso MT, Scardocci A, Guidi F, Zini G, Di Mario A, Pagano L, Hohaus S, Leone G: Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes. Blood 2004;103:698–700.
13.
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD: The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Mod Pathol 2000;13:193–207.
14.
Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821–9826.
15.
Kong WJ, Zhang S, Guo C, Zhang S, Wang Y, Zhang D: Methylation-associated silencing of death-associated protein kinase gene in laryngeal squamous cell cancer. Laryngoscope 2005;115:1395–1401.
16.
Wickremasinghe RG, Hoffbrand AV: Biochemical and genetic control of apoptosis: relevance to normal hematopoiesis and hematological malignancies. Blood 1999;93:3587–3600.
17.
Kliche KO, Höffken K: The role of apoptosis in hematologic malignancies and modulation of apoptosis as a new therapeutic approach. J Cancer Res Clin Oncol 1999;125:226–231.
18.
Cohen O, Feinstein E, Kimchi A: DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity. EMBO J 1997;16:998–1008.
19.
Jang CW, Chen CH, Chen CC, Chen JY, Su YH, Chen RH: TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat Cell Biol 2002;4:51–58.
20.
Kissil JL, Feinstein E, Cohen O, Jones PA, Tsai YC, Knowles MA, Eydmann ME, Kimchi A: DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene. Oncogene 1997;15:403–407.
21.
Esteller M, Sanchez-Cespedes M, Rosell R, Sidransky D, Baylin SB, Herman JG: Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res 1999;59:67–70.
22.
Sanchez-Cespedes M, Esteller M, Wu L, Nawroz-Danish H, Yoo GH, Koch WM, Jen J, Herman JG, Sidransky D: Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res 2000;60:892–895.
23.
Bialik S, Kimchi A: The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem 2006;75:189–210.
24.
Qian J, Yao DM, Lin J, Wang YL, Han LX, Xu WR, Wu CY: Methylation of DAPK1 promoter: frequent but not an adverse prognostic factor in myelodysplastic syndrome. Int J Lab Hematol 2010;32:74–81.
25.
Corey SJ, Minden MD, Barber DL, Kantarjian H, Wang JC, Schimmer AD: Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer 2007;7:118–129.
26.
Boultwood J, Wainscoat JS: Gene silencing by DNA methylation in haematological malignancies. Br J Haematol 2007;138:3–11.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.