Epigenetic silencing of tumor suppressor long non-coding RNA BM742401 in chronic lymphocytic leukemia.
BM742401 is a tumor suppressor lncRNA downregulated in gastric cancer. As the promoter region and the entire transcript are embedded in a CpG island, we postulated that BM742401 is a tumor suppressor lncRNA inactivated by DNA methylation in chronic lymphocytic leukemia (CLL). The promoter of BM742401 was unmethylated in normal controls including three each of normal bone marrow, peripheral blood buffy coats, and CD19-sorted peripheral B-cells, but methylated in four (57.1%) CLL cell lines. Methylation of BM742401 correlated inversely with expression. In the completely methylated WAC3CD5+ CLL cells, 5-Aza-2'-deoxycytidine treatment led to promoter demethylation and re-expression of BM742401 transcript. Functionally, stable overexpression of BM742401 resulted in inhibition of cellular proliferation and enhanced apoptosis through caspase-9-dependent intrinsic but not caspase-8-dependent extrinsic apoptosis pathway, suggesting a tumor suppressor role of BM742401 in CLL. In primary CLL samples, methylation of BM742401 was detected in 43/98 (43.9%) of patients. Moreover, among CLL patients with standard-risk cytogenetic aberrations, methylation of BM742401 correlated with advanced Rai stage (≥ stage 2)(P = 0.002). Furthermore, BM742401 methylation was associated with miR-129-2 methylation (P = 0.05). BM742401 is a tumor suppressor lncRNA frequently methylated in CLL. The mechanism of BM742401 as a tumor suppressor warrants further studies.
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Lu Qian
LQ
Wang
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Kwan Yeung
KY
Wong
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Zhen Hai
ZH
Li
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Chor Sang
CS
Chim
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016022:Case-Control Studies; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D004791:Enzyme Inhibitors; D035683:MicroRNAs; C541915:Mirn129 microRNA, human; D062085:RNA, Long Noncoding; D000077209:Decitabine; D015254:DNA Modification Methylases; C506433:CASP9 protein, human; D053453:Caspase 9; D001374:Azacitidine
BM742401; DNA methylation; chronic lymphocytic leukemia; lncRNA; tumor suppressor
Oncotarget. 2015 Dec 29;6(42):44422-36
26517243
Genes Dev. 1999 Oct 1;13(19):2514-26
10521396
PLoS Genet. 2013 Apr;9(4):e1003373
23593011
Leuk Res. 1999 Feb;23(2):127-36
10071128
Leuk Lymphoma. 2013 Aug;54(8):1769-79
23297799
Blood. 2011 Jan 20;117(3):862-71
21098398
J Clin Endocrinol Metab. 2003 Nov;88(11):5119-26
14602737
Cell Death Differ. 1999 Feb;6(2):99-104
10200555
Cancer Res. 2009 Dec 1;69(23 ):9038-46
19887623
Methods. 2001 Dec;25(4):402-8
11846609
J Transl Med. 2014 Feb 22;12:52
24559316
Blood. 2008 Jun 15;111(12):5446-56
18216293
Nature. 2014 Mar 27;507(7493):455-61
24670763
Cancer Res. 1997 Mar 1;57(5):837-41
9041182
J Cell Mol Med. 2011 Dec;15(12):2760-7
21323860
N Engl J Med. 2008 Mar 13;358(11):1148-59
18337604
Cancer Res. 1995 Oct 15;55(20):4531-5
7553622
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
12434020
Nat Rev Genet. 2011 Nov 18;12(12):861-74
22094949
Mol Cancer. 2013 Dec 27;12:173
24373626
Leukemia. 1994 Mar;8(3):476-84
8127151
J Biol Chem. 1999 Apr 23;274(17):11549-56
10206961
Exp Mol Med. 2013 Jul 12;45:e31
23846333
PLoS One. 2013;8(2):e53823
23405074
Cancer Discov. 2011 Oct;1(5):391-407
22096659
Leukemia. 2015 Oct;29(10):2015-23
25971364
J Mol Endocrinol. 2012 Apr 02;48(3):R45-53
22393162
Cancer Discov. 2014 Mar;4(3):348-61
24356097
Carcinogenesis. 2010 Apr;31(4):745-50
20118199
PLoS One. 2011;6(7):e22129
21811562
Mol Cell. 2010 Jun 11;38(5):662-74
20541999
Cell Cycle. 2010 May;9(9):1809-18
20404570
Oncoimmunology. 2012 Jan 1;1(1):18-27
22720208
J Hum Genet. 2006;51(9):832-8
16897188
Leukemia. 2007 Dec;21(12):2527-36
17882284
Cell. 2006 Dec 15;127(6):1209-21
17174895
J Hematol Oncol. 2013 Feb 14;6:16
23406679
Cell Death Differ. 2009 Jul;16(7):935-8
19528949
Cell. 2009 Feb 20;136(4):629-41
19239885
PLoS One. 2011 Apr 22;6(4):e19027
21544199
J Clin Pathol. 2008 Nov;61(11):1214-9
18765431
Nature. 2010 Apr 15;464(7291):1071-6
20393566
Nat Rev Genet. 2009 Mar;10(3):155-9
19188922
Proc Natl Acad Sci U S A. 2007 May 8;104(19):8053-8
17463088