IL-1 receptor antagonism reveals a yin- yang relationship between NFκB and interferon signaling in chronic lymphocytic leukemia

• 成果类型: Article
• 署名作者: Luo, Yuxuan; Su, Boyang; Hung, Vincent; Luo, Yuhan; Shi, Yonghong; Wang, Guizhi; de Graaf, Dennis; Dinarello, Charles A.; Spaner, David E.
• 署名单位: University of Toronto; Sunnybrook Research Institute; Sunnybrook Health Science Center; University of Toronto; University of Toronto; University of Colorado System; University of Colorado Anschutz Medical Campus; University of Colorado Denver; University of Bonn; Radboud University Nijmegen; University of Toronto; University of Toronto
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14159
• DOI: 10.1073/pnas.2405644121
• 发表日期: 2024-08-13
• 关键词: c-myc; interleukin-1; alpha; expression; cells; mitochondria; inhibition; reduction; anakinra; kinase

摘要

Nuclear factor kappa B (NF kappa B) is a pathogenic factor in chronic lymphocytic leukemia (CLL) that is not addressed specifically by current therapies. NF kappa B 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 kappa B 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 kappa B 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 kappa B and oxidative stress in the leukemia cells. However, inhibition of NF kappa B 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 cellsAcirc; in vitroAcirc; 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.