title: Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway.
abstract: 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.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
authors.forename: Sampath
authors.initials: S
authors.lastname: Ramachandiran
authors.forename: Arsene
authors.initials: A
authors.lastname: Adon
authors.forename: Xiangxue
authors.initials: X
authors.lastname: Guo
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Huichen
authors.initials: H
authors.lastname: Wang
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
authors.forename: Ustun R
authors.initials: UR
authors.lastname: Sunay
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Young
authors.forename: Theresa
authors.initials: T
authors.lastname: Brown
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Mar
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: Karen P
authors.initials: KP
authors.lastname: Mann
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Natkunam
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.forename: Harold I
authors.initials: HI
authors.lastname: Saavedra
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.forename: Leon
authors.initials: L
authors.lastname: Bernal-Mizrachi
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D018385:Centrosome / Q000378:metabolism; D043171:Chromosomal Instability; D002877:Chromosomes, Human / Q000235:genetics*; D056767:Cyclin G2 / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D059785:Karyotype; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D056767:Cyclin G2; D004317:Doxorubicin; D016328:NF-kappa B; D009687:Nuclear Proteins; D014157:Transcription Factors; C101593:CCNG2 protein, human; C469991:DDIT4 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins
keywords: NF-κB; chromosome stability; diffuse large cell lymphoma