Mohanty Suchismita, Mohanty Atish, Sandoval Natalie, Tran Thai, Bedell Victoria, Wu Jun, Scuto Anna, Murata-Collins Joyce, Weisenburger Dennis D, Ngo Vu N
a Division of Hematopoietic Stem Cell and Leukemia Research , Beckman Research Institute , Duarte , CA , USA.
b Irell & Manella Graduate School of Biological Sciences , Duarte , CA , USA.
Leuk Lymphoma. 2017 Mar;58(3):676-688. doi: 10.1080/10428194.2016.1198958. Epub 2016 Jun 24.
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.
套细胞淋巴瘤（MCL）中细胞周期蛋白D1（CCND1）表达水平升高与化疗耐药相关的侵袭性临床表现有关，但对于这个重要的原癌基因如何导致MCL耐药却知之甚少。在此，我们发现RNA干扰介导的CCND1缺失可增加人MCL细胞系UPN-1和JEKO-1中的半胱天冬酶-3活性并诱导细胞凋亡。体外和异种移植研究表明，MCL细胞中CCND1缺失的毒性作用可能是由于DNA损伤标志物组蛋白H2AX磷酸化增加所致。DNA纤维分析表明，CCND1缺失后复制起始失调是DNA损伤的潜在原因。最后，与细胞周期蛋白依赖性激酶4的缺失或抑制相反，CCND1缺失增加了MCL细胞对复制抑制剂羟基脲和阿糖胞苷的化学敏感性。我们的研究结果对于CCND1作为标准化疗难治的MCL患者的潜在治疗靶点具有重要意义。
