Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF‐κB pathway

• Published in: International journal of cancer 2015-05, Vol.136 (10), p.2341-2351
• 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: Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Nucleus - genetics; Centrosome - metabolism; Chromosomal Instability; chromosome stability; Chromosomes, Human - genetics; Cyclin G2 - metabolism; diffuse large cell lymphoma; DNA Damage; DNA Repair - drug effects; Doxorubicin - pharmacology; Humans; Karyotype; Lymphoma, Large B-Cell, Diffuse - genetics; Molecular Sequence Data; NF-kappa B - metabolism; NF‐κB; Nuclear Proteins - metabolism; Signal Transduction - drug effects; Transcription Factors - metabolism
• 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‐κB 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‐κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF‐κB 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‐κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53‐independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF‐κB sites to their promoter region. Overall, these results indicate that the noncanonical NF‐κB 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‐κB signaling. Both canonical and noncanonical NF‐κB 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‐κB signaling suppresses chromosome instability in DLBCL through the regulation of DNA damage and centrosome duplication. Those effects occurred via direct modulation of GADD45α, REDD1 and cyclin G2 expression. The data suggest that targeting noncanonical NF‐κB activation could be an effective therapeutic strategy in DLBCL.