THE ROLE OF DNA SENSOR SIGNALLING PATHWAY IN LYMPHOMA

Abstract

Organisms are constantly threatened by the invasion of viruses and have evolved systems of immune defense to eliminate viruses in the body. Intracellular viral infections are detected primarily by immune recognition of viral nucleic acids. Many intracellular DNA sensors induce the expression of pro-inflammatory cytokines and type I interferons (IFN) through the activation of the transcription factors including IFN regulatory factor 3 (IRF3). Interestingly, we found evidence that the same defense mechanisms are implicated in protecting organisms from cancer. We discovered that B-cell lymphomas and many tumor cell lines of various origin constitutively express cytosolic DNA as a consequence of drug- or oncogene-induced nuclear DNA damage. The expression of cytosolic DNA correlated with the activation of IRF3, suggesting that cytosolic DNA is detected by DNA sensors in tumor cells. Activation of IRF3 induced the expression of ligands for NKG2D, which regulates the ability of immune cells to recognize and eliminate tumors. Finally, we found that the DNA sensor Z-DNA binding protein (ZBP1) regulates B-cell lymphomagenesis. In summary, the data suggest pathogen recognition systems play a hitherto unknown role in tumorigenesis and immunosurveillance of cancer.