The Journal of Experimental Medicine
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doi:10.1084/jem.20072102
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© Liu et al.
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ARTICLE

 Transvection mediated by the translocated cyclin D1 locus in mantle cell lymphoma

Hui Liu1,2, Jing Huang1, Jin Wang1,2, Shuguang Jiang1,2, Alexis S. Bailey1,2, Devorah C. Goldman1,2, Markus Welcker3, Victoria Bedell4, Marilyn L. Slovak4, Bruce Clurman3, Mathew Thayer2, William H. Fleming1,2, and Elliot Epner1,2

1 Center for Hematologic Malignancies, Oregon Cancer Institute, Portland, OR 97239
2 Department of Medicine, Oregon Health and Science University (OHSU), Portland, OR 97239
3 Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109
4 Department of Cytogenetics, City of Hope National Medical Center, Duarte, CA 91010

CORRESPONDENCE Elliot Epner: epnere{at}ohsu.edu

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.

Abbreviations used: CCND1, cyclin D1; ChIP, chromatin immunoprecipitation; CTCF, CCCTC binding factor; FISH, fluorescent in situ hybridization; immunoFISH, immunofluorescent FISH; LCL, lymphocyte cell line; LCR, locus control region; MCL, mantle cell lymphoma; MM, multiple myeloma; MSP, methylation-specific PCR; MTC, major translocation cluster; NPM, nucleophosmin; Pol II, RNA polymerase II; shRNA, short hairpin RNA; TUNEL, Tdt-mediated dUTP-biotin nick-end labeling.

H. Liu and J. Huang contributed equally to this paper.

H. Liu's present address is Nimblegen Systems, Madison, WI 53711.

© 2008 Liu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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