Flipping the cyclin D1 switch in mantle cell lymphoma.
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.
Penn State Hershey Cancer Institute, Experimental Therapeutics A - CH74, Room T3319, 500 University Drive, Hershey, PA 17033-0850, USA.
Zainul
Z
Hasanali
Kamal
K
Sharma
Elliot
E
Epner
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006657:Histones / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D014158:Transcription, Genetic / Q000187:drug effects; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D006657:Histones; D019938:Cyclin D1