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Flipping the cyclin D1 switch in mantle cell lymphoma
Zainul Hasanali1, Kamal Sharma, Elliot Epner
1Penn State Hershey Cancer Institute, Experimental Therapeutics A - CH74, Room T3319, 500 University Drive, Hershey, PA 17033-0850, USA.
Best Practice & Research. Clinical Haematology
|June 13, 2012
Summary
Mantle cell lymphoma (MCL) is driven by a specific genetic translocation that epigenetically activates cyclin D1 (CCND1) expression. This epigenetic mechanism offers new therapeutic targets for treating this aggressive B cell lymphoma.
Area of Science:
- Oncology
- Hematology
- Epigenetics
Background:
- Mantle cell lymphoma (MCL) is a rare, aggressive B cell non-Hodgkin lymphoma with no established standard of care.
- MCL is characterized by the t(11;14) translocation, which involves the cyclin D1 (CCND1) gene, crucial for cell cycle regulation.
- CCND1 is aberrantly expressed in MCL, unlike in normal B cells, contributing to lymphomagenesis.
Purpose of the Study:
- To elucidate the epigenetic mechanisms underlying CCND1 deregulation in MCL.
- To establish the rationale for targeting epigenetic modifications and CCND1 in MCL therapy.
Main Methods:
- Analysis of the t(11;14) translocation in MCL cells.
- Investigation of DNA methylation status of enhancer elements (Eμ, 3' Cα) and upstream regions of the CCND1 gene.
- Assessment of histone modifications, specifically hyperacetylation, around the translocation site.
Main Results:
- The t(11;14) translocation juxtaposes IgH enhancer elements (Eμ, 3' Cα) to the CCND1 gene.
- Hypomethylation of these enhancer elements and upstream regions was observed on the translocated allele.
- Histone hyperacetylation, indicative of active chromatin, was found surrounding the translocation.
Conclusions:
- The t(11;14) translocation is an epigenetic event leading to the deregulated transcription of CCND1 in MCL.
- Epigenetic dysregulation provides a strong rationale for developing novel epigenetic and targeted CCND1 therapies.
- These targeted approaches hold promise for overcoming treatment resistance and achieving durable remissions in MCL patients.
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