Flipping the cyclin D1 switch in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is a rare, aggressive subtype of B cell NHL for which there is no standard of care. It is characterized by the t(11;14) translocation, implicating cyclin D1 (CCND1) in its pathogenesis. Cyclin D1 is one of a family of 3 unlinked D type cyclin genes, CCND1, 2, 3. CCND1 is not expressed in normal B cells. Deregulated expression occurs as a result of juxtaposition of cis IgH enhancer elements, Eμ and 3' Cα, to the cyclin D1 gene. These enhancer elements and regions upstream of the CCND1 gene are hypomethylated on the translocated allele. Histones surrounding the translocation have shown hyperacetylation as well, a hallmark of transcriptionally active chromatin. The t(11;14) translocation is an epigenetic event, leading to cyclin D1 deregulated transcription. These findings provide the rationale for the use of epigenetic and targeted cyclin D1 therapies to overcome resistance and induce durable remissions in MCL.