Overexpression of CDCA2 in Diffuse Large B-Cell Lymphoma Promotes Cell Proliferation and Bortezomib Sensitivity

Abstract

Numerous clinical trials have attempted to improve first-line R-CHOP treatment of diffuse large B-cell lymphoma (DLBCL) through the addition or substitution of drugs. The REMoDL-B trial, testing the addition of bortezomib (RB-CHOP), revealed that ABC and molecular high-grade DLBCL patients benefit from bortezomib. The aim of this study was to achieve a better understanding of the bortezomib response in DLBCL through a functional investigation of clinically identified markers. A retrospective analysis of transcriptional and clinical data from the REMoDL-B trial was conducted to identify genes associated with bortezomib response, identifying CDCA2. DLBCL patients with high expression of CDCA2 had a superior survival outcome when treated with RB-CHOP in comparison to R-CHOP, whereas no difference in outcome was observed for patients with low CDCA2. Moreover, CDCA2 was found to be overexpressed in DLBCL compared to non-malignant tissue, and to have higher levels in GCB and MYC/BCL2 double-expressor patients. Functional in vitro and in vivo studies revealed that knockout of CDCA2 decreased DLBCL cell proliferation and a bortezomib dose–response analysis showed less sensitivity in CDCA2 knockout cells compared to control cells. This study shows that DLBCL patients with high CDCA2 expression benefitted from the addition of bortezomib to R-CHOP and functional studies documented a direct impact of CDCA2 on the bortezomib response in DLBCL cells.