BIRC3 Expression Predicts CLL Progression and Defines Treatment Sensitivity via Enhanced NF-κB Nuclear Translocation

Clin Cancer Res. 2019 Mar 15;25(6):1901-1912. doi: 10.1158/1078-0432.CCR-18-1548. Epub 2018 Nov 28.


Purpose: Chronic lymphocytic leukemia (CLL) pathophysiology is characterized by a complex crosstalk of tumor cells with the microenvironment. In this regard, NF-κB signaling is considered as important signaling axis, with a variety of key molecules aberrantly expressed or genetically altered in patients with CLL. One of these molecules is BIRC3 (cIAP2), a central regulator of noncanonical NF-κB signaling that serves as pathway brake in the absence of microenvironmental signals. However, the contribution of BIRC3 expression to CLL progression and potential therapeutic implications is unknown.Experimental Design: We analyzed the role of BIRC3 mRNA expression in primary CLL samples in correlation to clinical datasets and used ex vivo assays to investigate functional consequences on the level of NF-κB signaling and downstream target gene regulation. For proof-of-principle experiments, we used genetically modified cell lines.

Results: We demonstrate that patients with CLL with low BIRC3 expression experience a more rapid disease progression, which coincides with an enhanced activation of canonical NF-κB target genes evidenced by an increased p65/Rel-B nuclear translocation ratio. As a consequence of enhanced canonical NF-κB target gene activation, both anti- and proapoptotic Bcl-2 family members were upregulated in BIRC3low primary CLL cells, which was associated with higher sensitivity to venetoclax treatment in vitro.

Conclusions: Here we show the impact of BIRC3 expression in CLL disease progression in the absence of BIRC3 mutations and show altered canonical NF-κB target gene activation with therapeutic implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis / genetics
  • Baculoviral IAP Repeat-Containing 3 Protein / genetics
  • Baculoviral IAP Repeat-Containing 3 Protein / metabolism*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Survival / genetics
  • Coculture Techniques
  • Datasets as Topic
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Leukemic
  • Gene Knockdown Techniques
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Male
  • Mice
  • Middle Aged
  • NF-kappa B / metabolism*
  • NIH 3T3 Cells
  • Proof of Concept Study
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction / genetics
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Treatment Outcome
  • Up-Regulation


  • Bridged Bicyclo Compounds, Heterocyclic
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • venetoclax