NFKBIA
NFKBIA stands for Nuclear Factor-Kappa B Inhibitor Alpha. It is a gene that encodes a protein known as IκBα (inhibitor of kappa B alpha), which is involved in regulating the activity of a transcription factor called nuclear factor-kappa B (NF-κB).
NF-κB is a protein complex that plays a crucial role in the regulation of genes involved in immune responses, inflammation, cell survival, and other processes. It acts as a transcription factor, meaning it helps control the expression of genes by binding to specific regions of DNA and influencing their activity.
The NFKBIA gene produces the IκBα protein, which acts as an inhibitor of NF-κB. IκBα binds to NF-κB and prevents its activation and translocation into the nucleus, where it can initiate gene expression. By inhibiting NF-κB, IκBα helps regulate the immune response and maintain a balance in inflammatory processes.
Mutations or alterations in the NFKBIA gene can affect the function of IκBα and the regulation of NF-κB. Dysregulation of NF-κB signaling has been implicated in various diseases, including inflammatory disorders, autoimmune conditions, and cancer. Research on NFKBIA and its relationship to these diseases is ongoing, and understanding its role may provide insights into potential therapeutic targets.
Bredel et al. demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and disproportionately present a recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas 1)
One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and its effects on NFKBIA. Patients were enrolled after signing an IRB-approved informed consent. Treatment was bortezomib 1.7 mg/m(2) IV on days 1, 4, and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m(2) PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m(2) on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycle post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumors than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be markers of the bortezomib effect on tumor 2).