Transvection mediated by the translocated cyclin D1 locus in mantle cell lymphoma.
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.
Liu
Hui
H
Center for Hematologic Malignancies, Oregon Cancer Institute, Portland, OR 97239, USA.
Huang
Jing
J
Wang
Jin
J
Jiang
Shuguang
S
Bailey
Alexis S
AS
Goldman
Devorah C
DC
Welcker
Markus
M
Bedell
Victoria
V
Slovak
Marilyn L
ML
Clurman
Bruce
B
Thayer
Mathew
M
Fleming
William H
WH
Epner
Elliot
E
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
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