title: microRNA-34b/c on chromosome 11q23 is aberrantly methylated in chronic lymphocytic leukemia.
abstract: A commonly deleted region in chronic lymphocytic leukemia (CLL) is the 11q22-23 region, which encompasses the ATM gene. Evidence suggests that tumor suppressor genes other than ATM are likely to be involved in CLL with del(11q). A microRNA (miR) cluster including the miR-34b and miR-34c genes is located, among other genes, within the commonly deleted region (CDR) at 11q. Interestingly, these miRs are part of the TP53 network and have been shown to be epigenetically regulated. In this study, we investigated the expression and methylation status of these miRs in a well-characterized cohort of CLL, including cases with/without 11q-deletion. We show that the miR-34b/c promoter was aberrantly hypermethylated in a large proportion of CLL cases (48%, 25/52 cases). miR-34b/c expression correlated inversely to DNA methylation (P = 0.003), and presence of high H3K37me3 further suppressed expression regardless of methylation status. Furthermore, increased miR-34b/c methylation inversely correlated with the presence of 11q-deletion, indicating that methylation and del(11q) independently silence these miRs. Finally, 5-azacytidine and trichostatin A exposure synergistically increased the expression of miR-34b/c in CLL cells, and transfection of miR-34b or miR-34c into HG3 CLL cells significantly increased apoptosis. Altogether, our novel data suggest that miR-34b/c is a candidate tumor suppressor that is epigenetically silenced in CLL.
authors.affiliation: Department of Internal Medicine/Hematology; Karolinska Institutet; Karolinska University Hospital Huddinge; Stockholm, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Deneberg
authors.affiliation: Institute of Biomedicine; Department of Clinical Chemistry and Transfusion Medicine; Sahlgrenska University Hospital; Göteborg, Sweden.
authors.forename: Meena
authors.initials: M
authors.lastname: Kanduri
authors.affiliation: Department of Internal Medicine/Hematology; Karolinska Institutet; Karolinska University Hospital Huddinge; Stockholm, Sweden.
authors.forename: Dina
authors.initials: D
authors.lastname: Ali
authors.affiliation: Department of Internal Medicine/Hematology; Karolinska Institutet; Karolinska University Hospital Huddinge; Stockholm, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Bengtzen
authors.affiliation: Department of Internal Medicine/Hematology; Karolinska Institutet; Karolinska University Hospital Huddinge; Stockholm, Sweden.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Karimi
authors.affiliation: Department of Internal Medicine/Hematology; Karolinska Institutet; Karolinska University Hospital Huddinge; Stockholm, Sweden.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Internal Medicine/Hematology; Karolinska Institutet; Karolinska University Hospital Huddinge; Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Kimby
authors.affiliation: Department of Immunology, Genetics and Pathology; Science for Life Laboratory; Uppsala University; Uppsala, Sweden.
authors.forename: Larry
authors.initials: L
authors.lastname: Mansouri
authors.affiliation: Department of Immunology, Genetics and Pathology; Science for Life Laboratory; Uppsala University; Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Department of Biomedicine and Nutrition; NOVUM; Karolinska Institutet; Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lennartsson
authors.affiliation: Department of Internal Medicine/Hematology; Karolinska Institutet; Karolinska University Hospital Huddinge; Stockholm, Sweden.
authors.forename: Sören
authors.initials: S
authors.lastname: Lehmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11 / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D017353:Gene Deletion; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: D000964:Antimetabolites, Antineoplastic; C415579:BTG4 protein, human; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C012589:trichostatin A; D001374:Azacitidine
keywords: DNA methylation; chronic lymphatic leukemia; epigenetics; micro-RNA