title: Epigenetic inactivation of the miR-124-1 in haematological malignancies.
abstract: miR-124-1 is a tumour suppressor microRNA (miR). Epigenetic deregulation of miRs is implicated in carcinogenesis. Promoter DNA methylation and histone modification of miR-124-1 was studied in 5 normal marrow controls, 4 lymphoma, 8 multiple myeloma (MM) cell lines, 230 diagnostic primary samples of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), MM, and non-Hodgkin's lymphoma (NHL), and 53 MM samples at stable disease or relapse. Promoter of miR-124-1 was unmethylated in normal controls but homozygously methylated in 4 of 4 lymphoma and 4 of 8 myeloma cell lines. Treatment of 5-Aza-2'-deoxycytidine led to miR-124-1 demethylation and re-expression of mature miR-124, which also associated with emergence of euchromatic trimethyl H3K4 and consequent downregulation of CDK6 in myeloma cells harboring homozygous miR-124-1 methylation. In primary samples at diagnosis, miR-124-1 methylation was absent in CML but detected in 2% each of MM at diagnosis and relapse/progression, 5% ALL, 15% AML, 14% CLL and 58.1% of NHL (p<0.001). Amongst lymphoid malignancies, miR-124-1 was preferentially methylated in NHL than MM, CLL or ALL. In primary lymphoma samples, miR-124-1 was preferentially hypermethylated in B- or NK/T-cell lymphomas and associated with reduced miR-124 expression. In conclusion, miR-124-1 was hypermethylated in a tumour-specific manner, with a heterochromatic histone configuration. Hypomethylation led to partial restoration of euchromatic histone code and miR re-expression. Infrequent miR-124-1 methylation detected in diagnostic and relapse MM samples showed an unimportant role in MM pathogenesis, despite frequent methylation found in cell lines. Amongst haematological cancers, miR-124-1 was more frequently hypermethylated in NHL, and hence warrants further study.
authors.affiliation: Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Kwan Yeung
authors.initials: KY
authors.lastname: Wong
authors.forename: Chi Chiu
authors.initials: CC
authors.lastname: So
authors.forename: Florence
authors.initials: F
authors.lastname: Loong
authors.forename: Lap Ping
authors.initials: LP
authors.lastname: Chung
authors.forename: William Wai Lung
authors.initials: WW
authors.lastname: Lam
authors.forename: Raymond
authors.initials: R
authors.lastname: Liang
authors.forename: George Kam Hop
authors.initials: GK
authors.lastname: Li
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
authors.forename: Chor Sang
authors.initials: CS
authors.lastname: Chim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D019337:Hematologic Neoplasms / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008223:Lymphoma / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics; D008297:Male; D008745:Methylation / Q000187:drug effects; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D001374:Azacitidine