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

R Piazza, V Magistroni, A Mogavero, F Andreoni… - Neoplasia, 2013 - Elsevier
R Piazza, V Magistroni, A Mogavero, F Andreoni, C Ambrogio, R Chiarle, L Mologni
Neoplasia, 2013Elsevier
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 …
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.
Elsevier