title: Transvection mediated by the translocated cyclin D1 locus in mantle cell lymphoma.
abstract: In mantle cell lymphoma (MCL) and some cases of multiple myeloma (MM), cyclin D1 expression is deregulated by chromosome translocations involving the immunoglobulin heavy chain (IgH) locus. To evaluate the mechanisms responsible, gene targeting was used to study long-distance gene regulation. Remarkably, these targeted cell lines lost the translocated chromosome (t(11;14)). In these MCL and MM cells, the nonrearranged cyclin D1 (CCND1) locus reverts from CpG hypomethylated to hypermethylated. Reintroduction of the translocated chromosome induced a loss of methylation at the unrearranged CCND1 locus, providing evidence of a transallelic regulatory effect. In these cell lines and primary MCL patient samples, the CCND1 loci are packaged in chromatin-containing CCCTC binding factor (CTCF) and nucleophosmin (NPM) at the nucleolus. We show that CTCF and NPM are bound at the IgH 3' regulatory elements only in the t(11;14) MCL cell lines. Furthermore, NPM short hairpin RNA produces a specific growth arrest in these cells. Our data demonstrate transvection in human cancer and suggest a functional role for CTCF and NPM.
authors.affiliation: Center for Hematologic Malignancies, Oregon Cancer Institute, Portland, OR 97239, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Shuguang
authors.initials: S
authors.lastname: Jiang
authors.forename: Alexis S
authors.initials: AS
authors.lastname: Bailey
authors.forename: Devorah C
authors.initials: DC
authors.lastname: Goldman
authors.forename: Markus
authors.initials: M
authors.lastname: Welcker
authors.forename: Victoria
authors.initials: V
authors.lastname: Bedell
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Slovak
authors.forename: Bruce
authors.initials: B
authors.lastname: Clurman
authors.forename: Mathew
authors.initials: M
authors.lastname: Thayer
authors.forename: William H
authors.initials: WH
authors.lastname: Fleming
authors.forename: Elliot
authors.initials: E
authors.lastname: Epner
mesh_terms: D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D018899:CpG Islands; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D005803:Genes, Immunoglobulin; D019940:Genes, bcl-1; D006801:Humans; D006822:Hybrid Cells; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D056741:Cyclin D; D016213:Cyclins; D004268:DNA-Binding Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000090243:Nucleophosmin