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Monoallelic Deletion of NFKBIA in Glioblastoma: When Less Is More

2011; Cell Press; Volume: 19; Issue: 2 Linguagem: Inglês

10.1016/j.ccr.2011.01.045

1878-3686

Amanda L. Rinkenbaugh, Albert S. Baldwin,

Signaling Pathways in Disease

Bredel et al., 2010Bredel M. Scholtens D.M. Yadav A.K. Alvarez A.A. Renfrow J.J. Chandler J.P. Yu I.L.Y. Carro M.S. Dai F. Tagge M.J. et al.N. Engl. J. Med. 2010; (in press. Published online December 22, 2010)https://doi.org/10.1056/nejmoa1006312Crossref Google Scholar recently identified a subset of glioblastomas that harbor monoallelic loss of NFKBIA, which negatively affects patient prognosis. This finding raises new questions as to the role of IκBα and NF-κB in glioblastoma, the relationship between EGFR and NF-κB signaling, and potential therapeutic targets. Bredel et al., 2010Bredel M. Scholtens D.M. Yadav A.K. Alvarez A.A. Renfrow J.J. Chandler J.P. Yu I.L.Y. Carro M.S. Dai F. Tagge M.J. et al.N. Engl. J. Med. 2010; (in press. Published online December 22, 2010)https://doi.org/10.1056/nejmoa1006312Crossref Google Scholar recently identified a subset of glioblastomas that harbor monoallelic loss of NFKBIA, which negatively affects patient prognosis. This finding raises new questions as to the role of IκBα and NF-κB in glioblastoma, the relationship between EGFR and NF-κB signaling, and potential therapeutic targets. When we think of mutations that promote cancer, those used for textbook and review examples, the NF-κB pathway does not get a lot of attention. Yet NF-κB is clearly established as an important mediator of oncogenesis (Karin, 2006Karin M. Nature. 2006; 441: 431-436Crossref PubMed Scopus (2807) Google Scholar), and mutations in the immediate regulatory pathways leading to NF-κB activation have been characterized (Courtois and Gilmore, 2006Courtois G. Gilmore T.D. Oncogene. 2006; 25: 6831-6843Crossref PubMed Scopus (369) Google Scholar). Importantly, well-established mutations that lead to cancer, such as activating mutations in Ras, function oncogenically through NF-κB activation (Bassères et al., 2010Bassères D.S. Ebbs A. Levantini E. Baldwin A.S. Cancer Res. 2010; 70: 3537-3546Crossref PubMed Scopus (135) Google Scholar, Mayo et al., 1997Mayo M.W. Wang C.Y. Cogswell P.C. Rogers-Graham K.S. Lowe S.W. Der C.J. Baldwin A.S. Science. 1997; 278: 1812-1815Crossref PubMed Scopus (484) Google Scholar, Meylan et al., 2009Meylan E. Dooley A.L. Feldser D.M. Shen L. Turk E. Ouyang C. Jacks T. Nature. 2009; 462: 104-107Crossref PubMed Scopus (416) Google Scholar). New work from Bredel et al., 2010Bredel M. Scholtens D.M. Yadav A.K. Alvarez A.A. Renfrow J.J. Chandler J.P. Yu I.L.Y. Carro M.S. Dai F. Tagge M.J. et al.N. Engl. J. Med. 2010; (in press. Published online December 22, 2010)https://doi.org/10.1056/nejmoa1006312Crossref Google Scholar demonstrates a fascinating monoallelic deletion of NFKBIA, in patient-derived glioblastoma multiforme (GBM). This gene encodes IκBα, a critical negative regulator of canonical NF-κB activation. The work suggests an interesting link between EGFR-induced signaling in GBM and the loss of IκBα. NF-κB is a transcription factor comprised of homo- and heterodimers of five subunits: p65/RelA, RelB, c-Rel, p105/p50, and p100/p52. Under basal conditions, IκB molecules (IκBα, β, and ɛ isoforms) sequester p65- and c-Rel-containing dimers in the cytoplasm. Full-length p100 and p105 contain similar motifs to IκB and must be processed to yield active p50 and p52 subunits. Upon activation by cytokines or other stimuli, the IKK complex phosphorylates IκB, leading to its proteasomal degradation, which leaves NF-κB free to accumulate in the nucleus to control target gene expression. Genes regulated by NF-κB promote cell proliferation and survival, underlying the importance of this transcription factor both in normal cell responses and in oncogenesis (Karin, 2006Karin M. Nature. 2006; 441: 431-436Crossref PubMed Scopus (2807) Google Scholar). Due to the integral involvement of NF-κB in promoting proliferation and the survival of cells of the hematopoietic system, it is not surprising that mutations in this pathway are observed in hematologic malignancies. c-Rel is often amplified in B cell malignancies and Hodgkin's lymphoma. Presumably, the abundance of c-Rel subunits overcomes the inhibitory mechanism of the IκBs, leading to constitutive activation. In both B cell and T cell leukemias/lymphomas, p100 truncations eliminate the inhibitory domains but leave p52 intact, resulting in a weakly oncogenic NF-κB subunit. The oncoprotein BCL-3, an IκB-related NF-κB coactivator that functions with the p50 and p52 subunits, is involved in the t(14:19) translocation in B cell CLL, ultimately increasing BCL-3 expression (Courtois and Gilmore, 2006Courtois G. Gilmore T.D. Oncogene. 2006; 25: 6831-6843Crossref PubMed Scopus (369) Google Scholar). Analysis of multiple myeloma samples shows increased NF-κB activity in the majority of patients, which occurs through alterations to a number of upstream NF-κB signaling molecules including BIRC2/3, CYLD, CD40, NFKB1, NFKB2, NIK, and TRAF3 (Annunziata et al., 2007Annunziata C.M. Davis R.E. Demchenko Y. Bellamy W. Gabrea A. Zhan F. Lenz G. Hanamura I. Wright G. Xiao W. et al.Cancer Cell. 2007; 12: 115-130Abstract Full Text Full Text PDF PubMed Scopus (748) Google Scholar). NF-κB-related mutations are not limited to leukemias. IKKɛ is a kinase related to IKKα and β, typically involved in innate immune signaling, but it has also been shown to be capable of canonical NF-κB pathway activation. Amplification of the genomic locus leading to IKKɛ overexpression has been documented in breast cancer cell lines and tumor samples (Boehm et al., 2007Boehm J.S. Zhao J.J. Yao J. Kim S.Y. Firestein R. Dunn I.F. Sjostrom S.K. Garraway L.A. Weremowicz S. Richardson A.L. et al.Cell. 2007; 129: 1065-1079Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar). Given the strong evidence of NF-κB subunits exhibiting oncogenic activity, it follows that the inhibitory IκBs would demonstrate tumor suppressor function. Consistent with this, as many as 10% of Hodgkin's lymphoma specimens show inactivation of both alleles of NFKBIA (Courtois and Gilmore, 2006Courtois G. Gilmore T.D. Oncogene. 2006; 25: 6831-6843Crossref PubMed Scopus (369) Google Scholar). By analyzing a large cohort of human glioblastomas, Bredel et al., 2010Bredel M. Scholtens D.M. Yadav A.K. Alvarez A.A. Renfrow J.J. Chandler J.P. Yu I.L.Y. Carro M.S. Dai F. Tagge M.J. et al.N. Engl. J. Med. 2010; (in press. Published online December 22, 2010)https://doi.org/10.1056/nejmoa1006312Crossref Google Scholar discovered heterozygous NFKBIA deletions in almost 25% of tumors. Interestingly, the loss of NFKBIA generally does not overlap with EGFR amplification, one of the most common genetic alterations in glioblastoma. In fact, EGFR-induced signaling is considered important for most, if not all, of glioma. Since it has been shown that EGFR can activate NF-κB, this mutual exclusivity suggests that EGFR and IκBα fall in the same pathway. Consistent with this idea, Bredel et al., 2010Bredel M. Scholtens D.M. Yadav A.K. Alvarez A.A. Renfrow J.J. Chandler J.P. Yu I.L.Y. Carro M.S. Dai F. Tagge M.J. et al.N. Engl. J. Med. 2010; (in press. Published online December 22, 2010)https://doi.org/10.1056/nejmoa1006312Crossref Google Scholar show that both NFKBIA-deleted tumors and EGFR-amplified tumors have a similar decrease in patient survival compared with those that are wild-type for both genes. They also demonstrate that expressing IκBα in NFKBIA-deleted or EGFR-amplified primary cultures decreased their viability, while cells that were wild-type for both were unaffected. Work from the Cancer Genome Atlas project identified four distinct subtypes in glioma: classical, mesenchymal, neural, and proneural (Verhaak et al., 2010Verhaak R.G.W. Hoadley K.A. Purdom E. Wang V. Qi Y. Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. et al.Cancer Cell. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (4339) Google Scholar). When the distribution of these two mutations is analyzed based on tumor subtype, those with EGFR amplification tend to cluster as classical, while those with NFKBIA deletion tend to fall into the three nonclassical subtypes. One interpretation is both of these mutations may cause NF-κB activation as a more general feature of GBM, regardless of subtype (Figure 1). In future work, novel mutations that affect this signaling axis to a similar end may be discovered in tumors that are wild-type for EGFR and IκBα. On the other hand, these mutations may have substantially different effects on the signaling in the tumor, manifested by the distinct segregation into different subtypes. Further studies to directly compare EGFR-amplified samples with NFKBIA-deleted ones will be useful in understanding the common characteristics and the unique properties of these subsets. While genomic NFKBIA deletion seems to be fairly common in GBM and has a significant impact on patient prognosis, there are several questions raised by this report that remain unanswered. First, the current study needs to be followed by functional validation in vitro and in vivo. As the level of NF-κB activity was not assessed in the tumors, it remains to be determined if NFKBIA deletion affects the NF-κB pathway. While it is known that glioma cell lines exhibit elevated levels of NF-κB activity, the source of this activation remains unclear. Additionally, comparing levels of NF-κB activity between tumors with NFKBIA deletion and EGFR amplification will help to determine if these two mutations produce a phenotypically similar disease. One particular endpoint to assess would be IL-6, a known NF-κB target gene. EGFRvIII, a constitutively active mutant EGFR, has been shown to increase IL-6 levels, which can act in a paracrine manner to activate wild-type EGFR on other tumor cells (Inda et al., 2010Inda M.M. Bonavia R. Mukasa A. Narita Y. Sah D.W.Y. Vandenberg S. Brennan C. Johns T.G. Bachoo R. Hadwiger P. et al.Genes Dev. 2010; 24: 1731-1745Crossref PubMed Scopus (374) Google Scholar). One could imagine that loss of IκBα in EGFR wild-type glioma could increase NF-κB activity and IL-6 levels, which can further activate EGFR. In the tumors analyzed by Bredel et al., 2010Bredel M. Scholtens D.M. Yadav A.K. Alvarez A.A. Renfrow J.J. Chandler J.P. Yu I.L.Y. Carro M.S. Dai F. Tagge M.J. et al.N. Engl. J. Med. 2010; (in press. Published online December 22, 2010)https://doi.org/10.1056/nejmoa1006312Crossref Google Scholar, monoallelic, but not biallelic, loss of NFKBIA was observed. There are several potential interpretations of this result, again requiring further analysis. Loss of one copy of NFKBIA appears to be advantageous to the tumor, possibly for the reasons described above and/or for other reasons. However, it seems to be disadvantageous to lose both copies, as it was not observed in any of the datasets Bredel et al. utilized. Perhaps this speaks to the need to retain some degree of control and inducibility over the NF-κB pathway (Figure 1). Another possibility is that IκBα has roles besides its most well-studied function as an NF-κB inhibitor and this is critical for oncogenesis or survival of cells of this particular lineage. Deletions of NFKBIA in glioblastomas reported by Bredel et al., 2010Bredel M. Scholtens D.M. Yadav A.K. Alvarez A.A. Renfrow J.J. Chandler J.P. Yu I.L.Y. Carro M.S. Dai F. Tagge M.J. et al.N. Engl. J. Med. 2010; (in press. Published online December 22, 2010)https://doi.org/10.1056/nejmoa1006312Crossref Google Scholar add to the documented mutations in the NF-κB pathway. Given the percentage of tumors with NFKBIA deletion and the impact on patient survival, this event seems to be significantly involved in glioblastoma development, potentially providing new targets for therapy. Future work requires further analysis of the downstream effects, particularly on the NF-κB pathway. Comparison of NFKBIA-deleted and EGFR-amplified tumors will be important in determining whether these two alterations lead to a common phenotype or if they characterize two distinct subsets of glioblastoma. Potentially, the implication is that NF-κB signaling could be centrally involved in all gliomas, although the mutations responsible may vary between subsets.