Due Hanne, Brogaard Asta, Issa Issa Ismail, Jakobsen Maja Zimmer, Sylvester Cathrine, Nøhr Anne Krogh, Thomsen Louiza Bohn, Thomsen Martin Kristian, Brøndum Rasmus Froberg, Dybkær Karen
Department of Hematology, Clinical Cancer Research Center, Aalborg University Hospital, 9000 Aalborg, Denmark.
Department of Clinical Medicine, Aalborg University, 9260 Gistrup, Denmark.
Int J Mol Sci. 2025 Jun 11;26(12):5596. doi: 10.3390/ijms26125596.
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 . DLBCL patients with high expression of 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 . Moreover, 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 decreased DLBCL cell proliferation and a bortezomib dose-response analysis showed less sensitivity in knockout cells compared to control cells. This study shows that DLBCL patients with high 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.
许多临床试验试图通过添加或替换药物来改善弥漫性大B细胞淋巴瘤（DLBCL）的一线R-CHOP治疗。REMoDL-B试验测试了添加硼替佐米（RB-CHOP）的效果，结果显示ABC和分子高级别DLBCL患者可从硼替佐米中获益。本研究的目的是通过对临床确定的标志物进行功能研究，更好地了解硼替佐米在DLBCL中的反应。对REMoDL-B试验的转录和临床数据进行回顾性分析，以确定与硼替佐米反应相关的基因，发现……与R-CHOP相比，接受RB-CHOP治疗时，高表达……的DLBCL患者生存结果更佳，而低……患者的生存结果无差异。此外，与非恶性组织相比，……在DLBCL中过表达，并且在生发中心B细胞（GCB）和MYC/BCL2双表达患者中水平更高。体外和体内功能研究表明，敲除……可降低DLBCL细胞增殖，硼替佐米剂量反应分析显示，与对照细胞相比，敲除……的细胞对硼替佐米的敏感性较低。本研究表明，高表达……的DLBCL患者可从R-CHOP联合硼替佐米治疗中获益，功能研究证明CDCA2对DLBCL细胞中硼替佐米反应有直接影响。
