Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-[kappa]B pathway

• Published in: International journal of cancer 2015-05, Vol.136 (10), p.2341
• Main Authors: Ramachandiran, Sampath, Adon, Arsene, Guo, Xiangxue, Wang, Yi, Wang, Huichen, Chen, Zhengjia, Kowalski, Jeanne, Sunay, Ustun R, Young, Andrew N, Brown, Theresa, Mar, Jessica C, Du, Yuhong, Fu, Haian, Mann, Karen P, Natkunam, Yasodha, Boise, Lawrence H, Saavedra, Harold I, Lossos, Izidore S, Bernal-Mizrachi, Leon
• Format: Article
• Language: English
• Subjects: Cancer; Chromosomes; Deoxyribonucleic acid; DNA; DNA damage; Lymphoma; Medical research
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29301

Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-[kappa]B pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-[kappa]B pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-[kappa]B pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-[kappa]B pathway execute these functions through the regulation of GADD45[alpha] and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45[alpha], REDD1 and cyclin G2 through direct binding of NF-[kappa]B sites to their promoter region. Overall, these results indicate that the noncanonical NF-[kappa]B pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach. What's new? Diffuse large B cell lymphoma (DLBCL) is a common malignancy that involves genomic instability and dysregulation of NF-[kappa]B signaling. Both canonical and noncanonical NF-[kappa]B signaling pathways play a role in DLBCL, acting either independently or concomitantly, though little is known about the noncanonical pathway. This study shows that noncanonical NF-[kappa]B signaling suppresses chromosome instability in DLBCL through the regulation of DNA damage and centrosome duplication. Those effects occurred via direct modulation of GADD45[alpha], REDD1 and cyclin G2 expression. The data suggest that targeting noncanonical NF-[kappa]B activation could be an effective therapeutic strategy in