Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia

Davide Rossi, Daniela Capello, Annunziata Gloghini, Silvia Franceschetti, Marco Paulli, Kishor Bhatia, Giuseppe Saglio, Umberto Vitolo, Stefano A. Pileri, Manel Esteller, Antonino Carbone, Gianluca Gaidano, Clara Deambrogi, Eva Berra, Michaela Cerri, Annarita Conconi, Chiara Vendramin, Marina Gutierrez, Barbara Botto

Research output: Contribution to journalArticlepeer-review


Background and Objectives. Aberrant promoter methylation targets CpG islands causing gene silencing. We explored aberrant promoter methylation of genes potentially involved in B-cell malignancies and encoding proteins implicated in DNA repair (O6-methylguanine-DNA methyltransferase, MGMT), detoxification of environmental xenobiotics (glutathione S-transferase P1, GSTP1), apoptosis regulation (death associated protein kinase, DAP-kand caspase 8, CASP8) and cell cycle control (p73). Design and Methods. Three hundred and seventeen B-cell malignancies were investigated by methylation-specific polymerase chain reaction (MSP) of MGMT, GSTP1, DAP-k, CASP8 and p73 genes. In selected cases, MSP results were matched to protein expression studies by immunohistochemistry or Western blotting. Results. DAP-k promoter methylation occurred at highest frequency in follicular lymphoma (85.0%) and MALT-lymphoma (72.2%). MGMTmethylation targeted both precursor B-cell neoplasia (23.8%) and mature B-cell tumors (27.6%). GSTP1 methylation was commonest in hairy cell leukemia (75.0%), follicular lymphoma (55.5%), Burkitt's lymphoma (52.0%), and MALT lymphoma (50.0%). Methylation of p73 and CASP8 was rare or absent. DAP-k and MGMT methylation caused absent protein expression. Interpretation and Conclusions. Methylation of MGMT, DAP-k and GSTP1 represents a major pathogenetic event in several B-cell malignancies. In follicular lymphoma and MALT lymphoma, frequent inactivation of the apoptosis extrinsic pathway through DAP-k methylation may reinforce the survival advantage already conferred by deregulation of the intrinsic apoptotic pathway. Inactivation of GSTP1 in gastric MALT lymphoma represents an additional mechanism favoring accumulation of reactive oxygen species and lymphomagenesis. Finally, the frequency of GSTP1 aberrant methylation in diffuse large B-cell lymphoma prompts studies aimed at verifying the prognostic impact of this epigenetic lesion in these lymphomas.

Original languageEnglish
Pages (from-to)154-164
Number of pages11
Issue number2
Publication statusPublished - Feb 2004


  • Aberrant methylation
  • B-cell
  • Leukemia
  • Lymphoma
  • Pathogenesis

ASJC Scopus subject areas

  • Hematology

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