Originally published as JCO Early Release 10.1200/JCO.2005.11.650 on May 2 2005

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Agrelo, R. Articles by Esteller, M. Search for Related Content PubMed PubMed Citation Articles by Agrelo, R. Articles by Esteller, M. Social Bookmarking                            What's this?

Inactivation of the Lamin A/C Gene by CpG Island Promoter Hypermethylation in Hematologic Malignancies, and Its Association With Poor Survival in Nodal Diffuse Large B-Cell Lymphoma

Ruben Agrelo, Fernando Setien, Jesus Espada, Maria Jesus Artiga, Maria Rodriguez, Alberto Pérez-Rosado, Abel Sanchez-Aguilera, Mario F. Fraga, Miguel Angel Piris, Manel Esteller

From the Cancer Epigenetics and Lymphoma Laboratories, Molecular Pathology Program, Spanish National Cancer Centre, Madrid, Spain

Address reprint requests to Manel Esteller, MD, PhD, Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain; e-mail: mesteller{at}cnio.es.

PURPOSE: Lamins support the nuclear envelope and provide anchorage sites for chromatin, but they are also involved in DNA synthesis, transcription, and apoptosis. Although the lack of expression of A-type lamins in lymphoma and leukemia has been reported, the mechanism was unknown. We investigated the possible role of CpG island hypermethylation in lamin A/C silencing and its prognostic relevance.

PATIENTS AND METHODS: The promoter CpG island methylation status of the lamin A/C gene, encoding the A-type lamins, was analyzed by bisulfite genomic sequencing and methylation-specific polymerase chain reaction in human cancer cell lines (n = 74; from 17 tumor types), and primary leukemias (n = 60) and lymphomas (n = 80). Lamin A/C expression was determined by reverse-transcription polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence.

RESULTS: Lamin A/C promoter CpG island methylation was found in hematologic malignancies: seven (50%) of 14 leukemia- and five (42%) of 13 lymphoma cell lines. The presence of hypermethylation was associated with the loss of gene expression while a demethylating agent restored expression. In primary malignancies, lamin A/C hypermethylation was present in 18% (nine of 50) of acute lymphoblastic leukemias and 34% (14 of 41) of nodal diffuse large B-cell lymphomas. The presence of lamin A/C hypermethylation in nodal diffuse large B-cell lymphomas correlated strongly with a decrease in failure-free survival (Kaplan-Meier, P = .0001) and overall survival (Kaplan-Meier, P = .0005).

CONCLUSION: Epigenetic silencing of the lamin A/C gene by CpG island promoter hypermethylation is responsible for the loss of expression of A-type lamins in leukemias and lymphomas. The finding that lamin A/C hypermethylation is associated with poor outcome in diffuse large B-cell lymphomas suggests important clinical implications.

Supported by the Health (FIS) and Science (I+D) Departments, Spanish Government; and Fundacion Telefonica.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				H. Taniguchi, A. F. Fernandez, F. Setien, S. Ropero, E. Ballestar, A. Villanueva, H. Yamamoto, K. Imai, Y. Shinomura, and M. Esteller Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies Cancer Res., November 1, 2009; 69(21): 8447 - 8454. [Abstract] [Full Text] [PDF]

				M. E. Hudson, I. Pozdnyakova, K. Haines, G. Mor, and M. Snyder Identification of differentially expressed proteins in ovarian cancer using high-density protein microarrays PNAS, October 30, 2007; 104(44): 17494 - 17499. [Abstract] [Full Text] [PDF]

				M. Esteller Epigenetic gene silencing in cancer: the DNA hypermethylome Hum. Mol. Genet., April 15, 2007; 16(R1): R50 - R59. [Abstract] [Full Text] [PDF]

				K. Maeshima, K. Yahata, Y. Sasaki, R. Nakatomi, T. Tachibana, T. Hashikawa, F. Imamoto, and N. Imamoto Cell-cycle-dependent dynamics of nuclear pores: pore-free islands and lamins J. Cell Sci., November 1, 2006; 119(21): 4442 - 4451. [Abstract] [Full Text] [PDF]

				R. Agrelo, W.-H. Cheng, F. Setien, S. Ropero, J. Espada, M. F. Fraga, M. Herranz, M. F. Paz, M. Sanchez-Cespedes, M. J. Artiga, et al. Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer PNAS, June 6, 2006; 103(23): 8822 - 8827. [Abstract] [Full Text] [PDF]