Suppression of minichromosome maintenance 7 expression sensitizes chronic lymphocytic leukemia cells to fludarabine

Abstract

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
• fludarabine
• minichromosome maintenance 7
• apoptosis
• drug resistance

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2018.1523400.

Additional information

Funding

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81473486 and 81270598), the Natural Science Foundations of Shandong Province (No. ZR2012HZ003), the Technology Development Projects of Shandong Province (No. 2014GSF118021), the Program of Shandong Medical Leading Talent, and the Taishan Scholar Foundation of Shandong Province.