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.
Keywords: Chronic lymphocytic leukemia; apoptosis; drug resistance; fludarabine; minichromosome maintenance 7.