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Cancer cells exist in a state of stress, but their IFN response is complex and not completely understood. This study investigated the role of autocrine IFN in human chronic lymphocytic leukemia (CLL) cells. CLL cells were found to make low amounts of IFN via TANK-binding kinase 1 pathways, but p-STAT1 and -STAT2 proteins along with IFN-stimulated genes that reflect IFN activation were variably downregulated in cultured CLL cells by the neutralizing IFNAR1 Ab anifrolumab. Patients with CLL were segregated into two groups based on the response of their leukemia cells to anifrolumab. Samples associated with more aggressive clinical behavior indicated by unmutated IGHV genes along with high CD38 and p-Bruton\u2019s tyrosine kinase expression exhibited responses to low amounts of IFN that were blocked by anifrolumab. Samples with more indolent behavior were unaffected by anifrolumab. Hypersensitivity to IFN was associated with higher expression of IFNAR1, MX1, STAT1, and STAT2 proteins and lower activity of negative regulatory tyrosine phosphatases. Autocrine IFN protected responsive CLL cells from stressful tissue culture environments and therapeutic drugs such as ibrutinib and venetoclax in vitro, in part by upregulating Mcl-1 expression. These findings suggest hypersensitivity to IFN may promote aggressive clinical behavior. Specific blockade of IFN signaling may improve outcomes for patients with CLL with higher-risk disease.<\/jats:p>","DOI":"10.4049\/jimmunol.2200199","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T13:32:20Z","timestamp":1666272740000},"page":"1662-1673","source":"Crossref","is-referenced-by-count":6,"title":["Enhanced IFN Sensing by Aggressive Chronic Lymphocytic Leukemia Cells"],"prefix":"10.1093","volume":"209","author":[{"given":"Tina YuXuan","family":"Luo","sequence":"first","affiliation":[{"name":"Biology Platform, Sunnybrook Research Institute , Toronto, Ontario,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghong","family":"Shi","sequence":"additional","affiliation":[{"name":"Biology Platform, Sunnybrook Research Institute , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guizhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Biology Platform, Sunnybrook Research Institute , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E","family":"Spaner","sequence":"additional","affiliation":[{"name":"Biology Platform, Sunnybrook Research Institute , Toronto, Ontario,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]},{"name":"Department of Medical Biophysics, University of Toronto , Toronto, Ontario,","place":["Canada"]},{"name":"Department of Medicine, University of Toronto , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,1]]},"reference":[{"key":"2025021008392683600_r1","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1097\/PPO.0000000000000412","article-title":"Bruton tyrosine kinase inhibitors: present and future","volume":"25","author":"Burger","year":"2019","journal-title":"Cancer J."},{"key":"2025021008392683600_r2","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1002\/ajh.25638","article-title":"Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic leukemia","volume":"94","author":"Munir","year":"2019","journal-title":"Am. 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