CTCF and Nucleophosmin Mediate Long Distance Cyclin D1 Deregulation in t(11;14) B Cell Malignancies.

Abstract

Translocations involving the immunoglobulin heavy chain gene locus (IgH) are common in B cell malignancies. One common target gene is cyclin D1, which is deregulated in most patients with mantle cell lymphoma (MCL) and 20–30% of patients with multiple myeloma (MM). Cyclin D1 is known not to be expressed in normal lymphocytes, yet is deregulated by IgH translocations and insertions. The molecular mechanisms of long distance cyclin D1 activation by IgH regulatory elements in B cell malignancies have been obscure. Chromatin immunoprecipitation (ChIP) assays demonstrated the presence of the CCCTC-binding factor (CTCF) at both the cyclin D1 promoter and 3′ IgH regulatory regions only in cyclin D1 expressing malignant B cell lines containing IgH translocations or insertions. The nucleolar protein nucleophosmin (B23; NPM), a newly identified CTCF interaction partner, exhibited a similar distribution in ChIP assays. Combined FISH/immunofluorescence labelling studies have shown the presence of the cyclin D1 loci colocalized with CTCF and nucleophosmin at the nucleolus in MCL cell lines and patient samples, “Knockdown” of NPM by shRNA shows a specific growth arrest in MCL and MM cell lines containing the t(11;14) and cell context dependent apoptosis. This growth arrest is not mediated by changes in cyclin D1 RNA or protein levels. Tethering of the cyclin D1 promoter to the 3′Cα IgH regulatory regions at the nucleolar membrane by CTCF/nucleophosmin allows spatial juxtaposition of the cyclin D1 promoter and 3′IgH regulatory elements and provides a mechanism for long distance cyclin D1 deregulation. Nucleophosmin is also identified as a target for novel therapies in t(11;14) B cell malignancies.