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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,13]]},"abstract":"<jats:p>Nuclear factor kappa B (NF\u03baB) is a pathogenic factor in chronic lymphocytic leukemia (CLL) that is not addressed specifically by current therapies. NF\u03baB is activated by inflammatory factors that stimulate toll-like receptors (TLRs) and receptors for interleukin-1 (IL-1) family members. IL-1 is considered a master regulator of inflammation, and IL-1 receptor signaling is inhibited by the IL-1 receptor antagonist anakinra. These considerations suggested that anakinra might have a role in the treatment of CLL. Consistent with this idea, anakinra inhibited spontaneous and TLR7-mediated activation of the canonical NF\u03baB pathway in CLL cells in vitro. However, CLL cells exhibited only weak signaling responses to IL-1 itself, and anakinra was found to inhibit NF\u03baB along with oxidative stress in an IL-1 receptor-independent manner. Anakinra was then administered with minimal toxicity to 11 previously untreated CLL patients in a phase I dose-escalation trial (NCT04691765). A stereotyped clinical response was observed in all patients. Anakinra lowered blood lymphocytes and lymph node sizes within the first month that were associated with downregulation of NF\u03baB and oxidative stress in the leukemia cells. However, inhibition of NF\u03baB was accompanied by upregulation of type 1 interferon (IFN) signaling, c-MYC-regulated genes and proteins, and loss of the initial clinical response. Anakinra increased IFN signaling and survival of CLL cells\u00c2 in vitro\u00c2 that were, respectively, phenocopied by mitochondrial antioxidants and reversed by IFN receptor blocking antibodies. These observations suggest that anakinra has activity in CLL and may be a useful adjunct for conventional therapies as long as compensatory IFN signaling is blocked at the same time.<\/jats:p>","DOI":"10.1073\/pnas.2405644121","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T13:39:39Z","timestamp":1723210779000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["IL-1 receptor antagonism reveals a yin-yang relationship between NF\u03baB and interferon signaling in chronic lymphocytic leukemia"],"prefix":"10.1073","volume":"121","author":[{"given":"YuXuan","family":"Luo","sequence":"first","affiliation":[{"name":"Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, Toronto M4N 3M5, Canada"},{"name":"Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"BoYang","family":"Su","sequence":"additional","affiliation":[{"name":"Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, Toronto M4N 3M5, Canada"},{"name":"Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Hung","sequence":"additional","affiliation":[{"name":"Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, Toronto M4N 3M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YuHan","family":"Luo","sequence":"additional","affiliation":[{"name":"Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, Toronto M4N 3M5, Canada"},{"name":"Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghong","family":"Shi","sequence":"additional","affiliation":[{"name":"Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, Toronto M4N 3M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guizhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, Toronto M4N 3M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"de Graaf","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Colorado Denver, Denver, CO 80045"},{"name":"Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn 53127, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5073-8316","authenticated-orcid":false,"given":"Charles A.","family":"Dinarello","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Colorado Denver, Denver, CO 80045"},{"name":"Department of Medicine, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Spaner","sequence":"additional","affiliation":[{"name":"Biological Science Platform, Sunnybrook Research Institute, Sunnybrook hospital, Toronto M4N 3M5, Canada"},{"name":"Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada"},{"name":"Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada"},{"name":"Department of Hematology, Odette Cancer Center, Toronto M4N 3M5, Canada"},{"name":"Department of Medicine, University of Toronto, Toronto M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.8"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022016272"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-08-870238"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2016.07.005"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-024-02224-8"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-0781"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.177808"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-12-754994"},{"key":"e_1_3_4_9_2","first-page":"1","article-title":"Interleukin-1 (IL-1) pathway","volume":"3","author":"Weber A.","year":"2010","unstructured":"A. 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