CTCF and Nucleophosmin Participate in Long Distance Cyclin D1 Deregulation in Mantle Cell Lymphoma.

Cyclin D1 expression in B cells is deregulated by long distance chromosome translocations involving the immunoglobulin heavy chain (IgH) locus in mantle cell lymphoma (MCL). Ge. Using chromatin immunoprecipitation (ChIP) assays, we show that the cyclin D1 (CCND1) loci in MCL cell lines and MCL patient samples are packaged in chromatin containing CCCTC binding factor (CTCF) and nucleophosmin (NPM). Using allelic chromatin immunoprecipitation (ChIP) assays, we demonstrate that both the translocated and nontranslocated cyclin D1 alleles bind both CTCF and NPM, while RNA polymerase II is only bound to the translocated allele. Sequential ChIP assays demonstrated CTCF and NPM binding at the cyclin D1 loci in MCL cells. By immunoFISH, we demonstrate that the translocated and nontranslocated cyclin D1 loci colocalize at the nucleolus. CTCF and NPM are bound at the IgH 3′ regulatory elements only in MCL cell lines. NPM shRNA effects a specific growth arrest in these cells. These data demonstrate a role for CTCF and NPM in long distance cyclin D1 deregulation in mantle cell lymphoma.