Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex

Rocco Piazza, Vera Magistroni, Angela Mogavero, Federica Andreoni, Chiara Ambrogio, Roberto Chiarle, Luca Mologni, Petra S. Bachmann, Richard B. Lock, Paola Collini, Giuseppe Pelosi, Carlo Gambacorti-Passerini

Research output: Contribution to journalArticlepeer-review

Abstract

BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation.

Original languageEnglish
Pages (from-to)511-522
Number of pages12
JournalNeoplasia (United States)
Volume15
Issue number5
DOIs
Publication statusPublished - 2013

ASJC Scopus subject areas

  • Cancer Research
  • Medicine(all)

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