Abstract
INTRODUCTION
Despite the universal use of temozolomide (TMZ) in GBM, many patients experience minimal benefit. Moreover, TMZ can be deleterious due to its mutagenic nature. These findings underline the importance of predicting which patients will benefit from TMZ. DATA: Bcl-3 was identified as being involved in cytotoxicity by TMZ due to its unique interaction with NF-κB residues modified following treatment. Up- and down-regulation of Bcl-3 in patient-derived glioma stem-like cells (GSCs) demonstrates that Bcl-3 blocks cytotoxicity by TMZ in vitro and in an intracranial PDX. Analysis of multiple public GBM datasets demonstrates that BCL3 mRNA expression is a marker of outcome, a finding confirmed on multivariate analysis incorporating MGMT promoter methylation, age and IDH mutation among other variables. Most notably, separation of patients in TCGA by treatment modality demonstrates that BCL3 is only informative in patients who received alkylating chemotherapy not untreated patients or those receiving ionizing radiation (IR) alone, a finding significant on multivariate analysis and validated in REMBRANDT. To examine Bcl-3 protein, TMAs were constructed incorporating 86 GBMs. Bcl-3 immunohistochemistry graded on a 4-tier system and dichotomized significantly separates patients into survival groups (P<0.0001; HR, 5.418; 95%CI, 2.747–9.647). In GBM, Bcl-3 mRNA and protein level is regulated by gene copy number determined in public datasets and in TMAs by FISH. CNAs of BCL3 occur due to changes directed to a broad region of 19q13, an area deleted in 20–40% of all types of glioma. Mechanistically, Bcl-3 promotes resistance by inducing mesenchymal differentiation via promoter-specific NF-κB dimer exchange, shown in GSCs and confirmed in TCGA GBM.
CONCLUSIONS
BCL3 is an independent predictor of response to TMZ in GBM whose expression is regulated by CNA targeted to 19q13 that inadvertently affect BCL3. Bcl-3 expression level represents a cell-intrinsic modulator of NF-κB activity that promotes mesenchymal differentiation and resistance to therapy.