title: 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.
abstract: OBJECTIVE
  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.
  
  
  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
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Epigenetics and Lymphoma Laboratories, Molecular Pathology Program, Spanish National Cancer Centre, Madrid, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: Agrelo
authors.forename: Fernando
authors.initials: F
authors.lastname: Setien
authors.forename: Jesus
authors.initials: J
authors.lastname: Espada
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Artiga
authors.forename: Maria
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Alberto
authors.initials: A
authors.lastname: Pérez-Rosado
authors.forename: Abel
authors.initials: A
authors.lastname: Sanchez-Aguilera
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Piris
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008198:Lymph Nodes / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D034904:Lamin Type A; C440308:lamin C; D001374:Azacitidine