title: Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex.
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: Department of Health Sciences, University of Milano, Bicocca, Monza, Italy. rocco.piazza@unimib.it
authors: Rocco
authors: R
authors: Piazza
authors: Vera
authors: V
authors: Magistroni
authors: Angela
authors: A
authors: Mogavero
authors: Federica
authors: F
authors: Andreoni
authors: Chiara
authors: C
authors: Ambrogio
authors: Roberto
authors: R
authors: Chiarle
authors: Luca
authors: L
authors: Mologni
authors: Petra S
authors: PS
authors: Bachmann
authors: Richard B
authors: RB
authors: Lock
authors: Paola
authors: P
authors: Collini
authors: Giuseppe
authors: G
authors: Pelosi
authors: Carlo
authors: C
authors: Gambacorti-Passerini
mesh_terms: D020121:5' Untranslated Regions; D000107:Acetylation; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex
chemical_list: D020121:5' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C497392:MECP2 protein, human; D008565:Membrane Proteins; D051783:Methyl-CpG-Binding Protein 2; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C012589:trichostatin A; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; D056264:Sin3 Histone Deacetylase and Corepressor Complex
references: Mol Cell. 2003 Sep;12(3):723-34
references: 14527417
references: J Biol Chem. 2002 Dec 20;277(51):49511-6
references: 12388545
references: Clin Immunol. 2003 Oct;109(1):80-8
references: 14585279
references: Genes Dev. 1999 Aug 1;13(15):1924-35
references: 10444591
references: Genes Dev. 1988 Sep;2(9):1136-43
references: 3192075
references: J Immunol. 2002 May 15;168(10):5024-31
references: 11994454
references: Trends Mol Med. 2002;8(4 Suppl):S43-8
references: 11927287
references: Cell Death Differ. 2003 Feb;10(2):211-7
references: 12700649
references: EMBO J. 2000 Aug 15;19(16):4342-50
references: 10944117
references: Blood. 2007 Oct 1;110(7):2600-9
references: 17537995
references: Immunogenetics. 2003 May;55(2):116-21
references: 12709835
references: Blood. 2004 Jun 15;103(12):4622-9
references: 14962911
references: Dev Cell. 2001 Nov;1(5):645-53
references: 11709185
references: Carcinogenesis. 2004 May;25(5):693-701
references: 14729589
references: Cell Cycle. 2008 Jan 1;7(1):39-44
references: 18196961
references: J Biol Chem. 2003 May 23;278(21):18811-6
references: 12646560
references: Blood. 2010 Oct 21;116(16):3013-22
references: 20647567
references: Neuron. 2003 Jun 19;38(6):899-914
references: 12818176
references: Br J Haematol. 2012 Nov;159(3):373-6
references: 22924699
references: Semin Oncol. 2005 Oct;32(5):521-30
references: 16210093
references: Mol Cell Biol. 2006 Feb;26(3):843-51
references: 16428440
references: Science. 1999 Nov 26;286(5445):1735-8
references: 10576740
references: Trends Genet. 2000 Apr;16(4):168-74
references: 10729832
references: Nat Genet. 1998 Jun;19(2):187-91
references: 9620779
references: Mol Cell Biol. 2001 Feb;21(3):854-64
references: 11154272
references: Curr Biol. 2000 Oct 5;10(19):1201-4
references: 11050388
references: Mol Cell Biol. 2007 Jul;27(13):4784-95
references: 17470557
references: PLoS Pathog. 2009 Jun;5(6):e1000492
references: 19557159
references: Curr Opin Genet Dev. 1993 Apr;3(2):226-31
references: 8504247
references: Blood. 2007 Jan 1;109(1):271-80
references: 16960149
references: Oncogene. 2003 Oct 2;22(43):6785-93
references: 14555991
references: Semin Oncol. 2003 Oct;30(5 Suppl 16):105-16
references: 14613031
references: Annu Rev Biochem. 2007;76:75-100
references: 17362198
references: Trends Biochem Sci. 2006 Feb;31(2):89-97
references: 16403636
references: Nat Rev Genet. 2010 Feb;11(2):109-23
references: 20084085
references: Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R65-76
references: 15809275
references: EMBO J. 2003 Dec 15;22(24):6653-64
references: 14657036
references: Cell. 2007 Feb 23;128(4):683-92
references: 17320506
references: Oncogene. 2007 Oct 25;26(49):7038-48
references: 17486061
references: Eur J Cancer. 2009 Jul;45(10):1877-89
references: 19403302
references: Immunity. 2002 Jun;16(6):759-67
references: 12121658
references: Oncogene. 2005 Feb 17;24(8):1348-58
references: 15608680
references: J Biol Chem. 2001 Sep 7;276(36):34115-21
references: 11441023
references: Nucleic Acids Res. 2003 Mar 15;31(6):1765-74
references: 12626718
references: Epigenetics. 2006 Apr-Jun;1(2):63-6
references: 17965604
references: Cancer Res. 2009 Nov 15;69(22):8611-9
references: 19887607
references: Clin Cancer Res. 2011 Apr 15;17(8):2140-8
references: 21415216
references: Genes Dev. 2006 Dec 1;20(23):3215-31
references: 17158741
references: Oncogene. 2005 Mar 31;24(14):2317-29
references: 15688014
references: Blood. 2010 Oct 7;116(14):2531-42
references: 20570860
references: Cell. 1997 May 2;89(3):349-56
references: 9150134
references: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6164-9
references: 15079075
references: Nucleic Acids Res. 1983 Oct 11;11(19):6883-94
references: 6314264