title: Aberrant interferon-signaling is associated with aggressive chronic lymphocytic leukemia.
abstract: The type I interferons (IFNs) normally suppress tumor growth by phosphorylating and activating the signal transducer and activator of transcription 1 (STAT1), but also briefly activate STAT3, which promotes cell growth. In chronic lymphocytic leukemia (CLL) cells, the duration of IFN-mediated STAT3 phosphorylation was found to exhibit significant interpatient variability and was prolonged in cells with high risk features, such as 11q- and 17p-deletions involving ataxia telangiectasia mutated (ATM) and p53. This aberrant signaling pattern was associated with a paradoxical increase in cell size and number in response to IFN and similar alterations in IFN-signaling and responses were seen in cell lines that developed in the absence of p53 or ATM. However, direct inhibition of p53 or ATM failed to cause these changes, and CLL cells with aggressive clinical features were found to also express high levels of reactive oxygen species (ROS), which decrease tyrosine phosphatase activity. Prolonged IFN-mediated STAT3 phosphorylation and lowered phosphatase activity could be reversed by antioxidants. These findings suggest that increased ROS levels may corrupt IFN-signaling processes in aggressive CLL cells, causing IFN to be used as a growth factor rather than a tumor suppressor. Antioxidants or STAT3 kinase inhibitors might improve the outcome of IFN therapy in CLL by restoring normal signaling.
authors.affiliation: Division of Molecular and Cellular Biology, Research Institute, Sunnybrook Health Sciences Center, Toronto, ON, Canada.
authors.forename: Jelena
authors.initials: J
authors.lastname: Tomic
authors.forename: Brian
authors.initials: B
authors.lastname: Lichty
authors.forename: David E
authors.initials: DE
authors.lastname: Spaner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012015:Reference Standards; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010703:Phorbol Esters; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D007372:Interferons; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases