a Department of Hematology , Shandong Provincial Hospital Affiliated with Shandong University , Jinan , Shandong , China.
b School of Medicine , Shandong University , Jinan , Shandong , China.
Leuk Lymphoma. 2019 May;60(5):1266-1274. doi: 10.1080/10428194.2018.1523400. Epub 2019 Feb 4.
Chronic lymphocytic leukemia (CLL) constitutes the largest percentage of adult leukemia cases in Western countries. Classically, fludarabine (Flu) is an effective drug used as a first-line therapy for CLL; however, Flu resistance limits its clinical effect. Minichromosome maintenance (MCM) complex components 2-7 exert important functions in maintaining genomic stability. Replication stress occurs upon dysregulation of MCM7, which potentiates malignant phenotypes. In this study, primary CLL cells and CLL-derived cell lines displayed elevated MCM7 expression. In CD40-stimulated primary CLL cells, MCM7 inhibition resulted in increased Flu-induced apoptosis and delayed repair of DNA damage. In the MEC-1 and EHEB cell lines, knockdown of MCM7 with lentivirus significantly inhibited cell proliferation and promoted cell cycle arrest at S phase. Moreover, MCM7 silencing sensitized both cell lines to Flu by increasing replication stress. The combination of Flu administration with MCM7 inhibition represents a novel approach to reverse Flu resistance in CLL.
慢性淋巴细胞白血病（CLL）构成了西方国家成人白血病病例的最大比例。经典地，氟达拉滨（Flu）是一种有效的药物，用作 CLL 的一线治疗药物；然而，Flu 耐药限制了其临床效果。微小染色体维持（MCM）复合物成分 2-7 在维持基因组稳定性方面发挥着重要作用。MCM7 的失调会导致复制应激，从而增强恶性表型。在这项研究中，原代 CLL 细胞和 CLL 衍生的细胞系显示出升高的 MCM7 表达。在 CD40 刺激的原代 CLL 细胞中，MCM7 抑制导致 Flu 诱导的细胞凋亡增加和 DNA 损伤修复延迟。在 MEC-1 和 EHEB 细胞系中，用慢病毒敲低 MCM7 显著抑制细胞增殖并促进 S 期细胞周期停滞。此外，沉默 MCM7 通过增加复制应激使这两种细胞系对 Flu 敏感。将 Flu 给药与 MCM7 抑制相结合代表了一种逆转 CLL 中 Flu 耐药的新方法。
