Transvection Mediated by the Translocated Cyclin D1 Locus in B Cell Malignancies.

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). The cyclin D1 locus represents a model locus to study the role of epigenetics in B cell malignancy. Cyclin D1 is known not to be expressed in normal lymphocytes, where the locus is DNA hypomethylated. In genetic variants that have lost the translocated chromosome, the cyclin D1 locus assumes a densely methylated configuration. Reintroduction of the translocated chromosome by somatic cell fusion reverts the methylated normal locus to a hypomethylated state in trans. Thus, the translocated chromosome exerts a trans DNA hypomethylating effect on the normal chromosome that resembles transvection in Drosophila. This is the first evidence of transvection in a human malignancy. Similar to transvection in Drosophila and paramutation in plants, evidence for pairing of the cyclin D1 loci and the participation of small RNA’s in this process has been obtained. Combined FISH/ immunofluorescent studies have shown the colocalization of both the normal and translocated chromosome 11’s at the nucleolus. Using chromatin immunoprecipitation assays, we show that CTCF and nucleophosmin are present at both the normal and translocated chromosomes in B cells expressing cyclin D1 but not in B lymphocytes. Tethering of the translocated and nontranslocated cyclin D1 loci by CTCF/nucleophosmin at the nucleolus provides physical and spatial juxtaposition of the cyclin D1 loci permissive for transvection.