Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway2014-10-30 00:01:09
International Journal of Cancer; 30 OCT 2014; DOI:10.1002/ijc.29301
Sampath Ramachandiran, Arsene Adon, Xiangxue Guo, Yi Wang, Huichen Wang, Zhengjia Chen, Jeanne Kowalski, Ustun R. Sunay, Andrew N. Young, Theresa Brown, Jessica C. Mar, Yuhong Du, Haian Fu, Karen P. Mann, Yasodha Natkunam, Lawrence H. Boise, Harold I. Saavedra, Izidore S. Lossos and Leon Bernal-Mizrachi
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-κB pathway, the precise role of the noncanonical NF-κB 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-κB pathway should be considered as an important component in DLBCL therapeutic approach.
Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype in the United States, accounting for approximately 25,000 cases per year. Genomic studies have identified two DLBCL subtypes that resemble normal cells from distinct stages of B cell differentiation, namely germinal center-like (GCB) and activated-B-cell-like (ABC) DLBCL. ABC DLBCL is characterized by aggressive clinical course and inferior overall survival. These unfavorable clinical characteristics are strongly associated with dysregulation of signals such as the NF-κB pathway. Both canonical and noncanonical NF-κB pathways are involved in DLBCL, either concomitantly or independent of one another. Although, advances have been made in understanding the role of the canonical NF-κB pathway in DLBCL, the precise role of its noncanonical counterpart remains to be established.
Mutations in NF-κB regulatory proteins are found in a significant number of ABC-DLBCL, indicating a substantial role for this signal in lymphomagenesis. Signals generated from NF-κB activating mutations in A20, CARD11, RANK and other genes results in phosphorylation of upstream activators, IKKγ and NIK. These subunits subsequently triggers the canonical and/or noncanonical NF-κB pathways by promoting processing of precursor proteins p105/NF-κB1 and p100/NF-κB2 to their corresponding mature forms, p50 and p52. Both mature proteins heterodimerize with other NF-κB members (p65/Rel-A, c-Rel, or Rel-B) and translocate to the nucleus where they regulate the expression of genes that influence B cell survival, proliferation, differentiation and immunoglobulin gene (Ig) editing.
Controlled genetic instability is inherent to the physiologic processes responsible for producing Ig diversity in B cells. Two members of the noncanonical NF-κB pathway, Rel B and NF-κB2, directly influence Ig editing by altering class switch recombination. For example, Rel-B is directly implicated in IL4-mediated immunoglobulin IgG1 isotype production. In addition, NF-κB2 inactivating mutations leads to deficiencies in late B cell differentiation and reduced immunoglobulin levels in common variable immunodeficiency patients and in transgenic mouse models.
Unlike its normal counterpart, DLBCL undergo inappropriate editing of the Ig and targets non-Ig genes. The resulting genomic instability increases cells susceptibility to acquire oncogenic mutations and chromosomal translocations in multiple genes such as MYC, BCL6, PIM1 and BCL2. Given the role of noncanonical NF-κB pathway in CSR, it is likely that this pathway regulates signals involved in controlling DLBCL genome integrity. Here, we demonstrate that activation of the noncanonical NF-κB pathway impacts chromosome stability in DLBCL by regulating genes involved in DNA repair, generation of reactive oxygen species and cell cycle control such as GADD45α, REDD1 and cyclin G2.
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Diffuse large cell lymphoma | NF-κB | chromosome stability