Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines. Issue 3 (4th March 2017)

• Record Type: Journal Article
• Authors: Mohanty, Suchismita; Mohanty, Atish; Sandoval, Natalie; Tran, Thai; Bedell, Victoria; Wu, Jun; Scuto, Anna; Murata-Collins, Joyce; Weisenburger, Dennis D.; Ngo, Vu N.
• Is Part Of: Leukemia & lymphoma. Volume 58:Issue 3(2017)
• Page Start: 676
• Page End: 688
• Publication Date: 2017-03-04
• Subjects: Chemoresistance -- cyclin D1 -- DNA damage -- mantle cell lymphoma -- replication stress; Leukemia -- Periodicals; Lymphomas -- Periodicals; 616.99419
• DOI: 10.1080/10428194.2016.1198958
• Languages: English
• ISSNs: 1042-8194

Abstract

Abstract: Elevated cyclin D1 (CCND1) expression levels in mantle cell lymphoma (MCL) are associated with aggressive clinical manifestations related to chemoresistance, but little is known about how this important proto-oncogene contributes to the resistance of MCL. Here, we showed that RNA interference-mediated depletion of CCND1 increased caspase-3 activities and induced apoptosis in the human MCL lines UPN-1 and JEKO-1. In vitro and xenotransplant studies revealed that the toxic effect of CCND1 depletion in MCL cells was likely due to increase in histone H2AX phosphorylation, a DNA damage marker. DNA fiber analysis suggested deregulated replication initiation after CCND1 depletion as a potential cause of DNA damage. Finally, in contrast to depletion or inhibition of cyclin-dependent kinase 4, CCND1 depletion increased chemosensitivity of MCL cells to replication inhibitors hydroxyurea and cytarabine. Our findings have an important implication for CCND1 as a potential therapeutic target in MCL patients who are refractory to standard chemotherapy.