Epigenetic gene silencing in acute promyelocytic leukemia

R. Villa, F. De Santis, A. Gutierrez, S. Minucci, P. G. Pelicci, L. Di Croce

Research output: Contribution to journalArticle

Abstract

The recent explosion in our knowledge of how chromatin organization modulates gene transcription has highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes - in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing - affect virtually every step in tumor progression. Intriguingly, methylation patterns are severely altered in tumors, with an overall hypomethylation of the genome and hypermethylation of islands of CpGs clusters within specific DNA regions. Though overexpression of DNA methyltransferases (DNMTs) has been proposed to be a mechanism for aberrant genome methylation, it does not explain the specific regional hypermethylation in cancer cells. We have analyzed the role of chromatin modifying activities in cell transformation using acute promyelocytic leukemia as a model system. This disease is caused by expression of the PML-RARα fusion protein, thus offering the opportunity of studying the mechanisms of leukemogenesis through molecular investigation of the activity of the directly transforming protein. Recent evidence suggests that PML-RARα as well as other leukemia-associated fusion proteins induce changes in the chromatin structure. Specifically, aberrant recruitment of different chromatin modifying enzymes to specific promoters induces DNA hypermethylation and heterochromatin formation, which consequentially leads to the transcriptional silencing of that genes. Importantly, these epigenetic modifications were found to contribute to the leukemogenic potential of PML-RARα. These observations suggest that epigenetic alterations could actively contribute to the development of APL and other hyperproliferative diseases.

Original languageEnglish
Pages (from-to)1247-1254
Number of pages8
JournalBiochemical Pharmacology
Volume68
Issue number6
DOIs
Publication statusPublished - Sep 15 2004

Keywords

  • 5-Aza-dC
  • acute promyelocytic leukemias
  • APL
  • DNA methyltransferase
  • DNMT
  • HDAC
  • histone deacetylase
  • MBDs
  • methyl-binding proteins
  • NCoR
  • nuclear corepressor
  • PML gene
  • promyelocytic leukemia
  • RAR
  • retinoic acid receptor
  • transcriptional repression domain
  • TRD

ASJC Scopus subject areas

  • Pharmacology

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