BCL3 expression promotes resistance to alkylating chemotherapy in gliomas

Sci Transl Med. 2018 Jul 4;10(448):eaar2238. doi: 10.1126/scitranslmed.aar2238.


The response of patients with gliomas to alkylating chemotherapy is heterogeneous. However, there are currently no universally accepted predictors of patient response to these agents. We identify the nuclear factor κB (NF-κB) co-regulator B cell CLL/lymphoma 3 (BCL-3) as an independent predictor of response to temozolomide (TMZ) treatment. In glioma patients with tumors that have a methylated O6-methylguanine DNA methyltransferase (MGMT) promoter, high BCL-3 expression was associated with a poor response to TMZ. Mechanistically, BCL-3 promoted a more malignant phenotype by inducing an epithelial-to-mesenchymal transition in glioblastomas through promoter-specific NF-κB dimer exchange. Carbonic anhydrase II (CAII) was identified as a downstream factor promoting BCL-3-mediated resistance to chemotherapy. Experiments in glioma xenograft mouse models demonstrated that the CAII inhibitor acetazolamide enhanced survival of TMZ-treated animals. Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • B-Cell Lymphoma 3 Protein
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics*
  • Carbonic Anhydrase II / metabolism
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Epithelial-Mesenchymal Transition / drug effects
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Glioma / drug therapy*
  • Glioma / genetics*
  • Humans
  • Multivariate Analysis
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic / genetics
  • Proportional Hazards Models
  • Protein Multimerization
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Survival Analysis
  • Temozolomide / pharmacology
  • Temozolomide / therapeutic use
  • Transcription Factor RelA / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Alkylating
  • B-Cell Lymphoma 3 Protein
  • BCL3 protein, human
  • Bcl3 protein, mouse
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Transcription Factor RelA
  • Transcription Factors
  • Carbonic Anhydrase II
  • Temozolomide