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Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex.
Neoplasia. 2013 May; 15(5):511-22.N

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.

Authors+Show Affiliations

Department of Health Sciences, University of Milano, Bicocca, Monza, Italy. rocco.piazza@unimib.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23633923

Citation

Piazza, Rocco, et al. "Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma Through an MeCP2/SIN3a Deacetylating Complex." Neoplasia (New York, N.Y.), vol. 15, no. 5, 2013, pp. 511-22.
Piazza R, Magistroni V, Mogavero A, et al. Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex. Neoplasia. 2013;15(5):511-22.
Piazza, R., Magistroni, V., Mogavero, A., Andreoni, F., Ambrogio, C., Chiarle, R., Mologni, L., Bachmann, P. S., Lock, R. B., Collini, P., Pelosi, G., & Gambacorti-Passerini, C. (2013). Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex. Neoplasia (New York, N.Y.), 15(5), 511-22.
Piazza R, et al. Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma Through an MeCP2/SIN3a Deacetylating Complex. Neoplasia. 2013;15(5):511-22. PubMed PMID: 23633923.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex. AU - Piazza,Rocco, AU - Magistroni,Vera, AU - Mogavero,Angela, AU - Andreoni,Federica, AU - Ambrogio,Chiara, AU - Chiarle,Roberto, AU - Mologni,Luca, AU - Bachmann,Petra S, AU - Lock,Richard B, AU - Collini,Paola, AU - Pelosi,Giuseppe, AU - Gambacorti-Passerini,Carlo, PY - 2012/10/22/received PY - 2013/02/12/revised PY - 2013/02/15/accepted PY - 2013/5/2/entrez PY - 2013/5/2/pubmed PY - 2013/12/16/medline SP - 511 EP - 22 JF - Neoplasia (New York, N.Y.) JO - Neoplasia VL - 15 IS - 5 N2 - 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. SN - 1476-5586 UR - https://www.unboundmedicine.com/medline/citation/23633923/Epigenetic_silencing_of_the_proapoptotic_gene_BIM_in_anaplastic_large_cell_lymphoma_through_an_MeCP2/SIN3a_deacetylating_complex_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23633923/ DB - PRIME DP - Unbound Medicine ER -