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

Hui Liu, Jing Huang, Jin Wang, Shuguang Jiang, Alexis S. Bailey, Devorah C. Goldman, Markus Welcker, Victoria Bedell, Marilyn L. Slovak, Bruce Clurman, Mathew Thayer, William H. Fleming, Elliot Epner

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23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1843-1858
Number of pages16
JournalJournal of Experimental Medicine
Volume205
Issue number8
DOIs
StatePublished - Aug 4 2008

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Liu, H., Huang, J., Wang, J., Jiang, S., Bailey, A. S., Goldman, D. C., Welcker, M., Bedell, V., Slovak, M. L., Clurman, B., Thayer, M., Fleming, W. H., & Epner, E. (2008). Transvection mediated by the translocated cyclin D1 locus in mantle cell lymphoma. Journal of Experimental Medicine, 205(8), 1843-1858. https://doi.org/10.1084/jem.20072102