Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2013-05, Vol.15 (5), p.511-IN17
• Main Authors: Piazza, Rocco, Magistroni, Vera, Mogavero, Angela, Andreoni, Federica, Ambrogio, Chiara, Chiarle, Roberto, Mologni, Luca, Bachmann, Petra S, Lock, Richard B, Collini, Paola, Pelosi, Giuseppe, Gambacorti-Passerini, Carlo
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions; Acetylation; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Case-Control Studies; Cell Line, Tumor; Cell Survival; Chromatin - metabolism; CpG Islands; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Silencing; Histone Deacetylase Inhibitors - pharmacology; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; Lymphoma, Large-Cell, Anaplastic - genetics; Lymphoma, Large-Cell, Anaplastic - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Methyl-CpG-Binding Protein 2 - metabolism; Oncology; Protein Processing, Post-Translational; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Repressor Proteins - metabolism
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.121784

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.