Abstract
Cyclin D1 expression in B cells is deregulated by chromosome translocations involving the immunoglobulin heavy chain (IgH) locus in mantle cell lymphoma (MCL). Gene targeting experiments produced MCL cell lines that had lost the translocated t(11;14) and no longer expressed cyclin D1. In these cyclin D1 (−) cells, the nonrearranged cyclin D1 (CCND1) locus reverts from CpG hypomethylated to hypermethylated. Reintroduction of the translocated chromosome by somatic cell hybrid fusion induces loss of methylation at the unrearranged CCND1 locus. Thus, the translocated chromosome exerts a transallelic effect on the unrearranged CCND1 locus in B cells that resembles transvection in Drosophilia. Control somatic cell fusion experiments with a nontranslocated cyclin D1 locus do not demonstrate transvection effects. We also have evidence for pairing of the translocated and nontranslocated cyclin D1 loci in MCL cell lines and MCL patient samples. This pairing is not related to DNA replication, as it is observed in flow sorted G1 cells and not in cyclin D1 expressing breast cancer cells or in B lymphocytes. In addition, to pairing of the cyclin D1 loci, we also have demonstrated translocation specific small RNAs in MCL cells upstream of the cyclin D1 gene.
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