JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL
Haselager, Marco V. and Thijssen, Rachel and Bax, Danique and Both, Demi and De Boer, Francien and Mackay, Simon and Dubois, Julie and Mellink, Clemens and Kater, Arnon P. and Eldering, Eric (2023) JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL. Molecular Oncology, 17 (6). pp. 1112-1128. ISSN 1878-0261 (https://doi.org/10.1002/1878-0261.13364)
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Abstract
Preventing or overcoming resistance to the Bcl‐2 inhibitor venetoclax is an emerging unmet clinical need in patients with chronic lymphocytic leukaemia (CLL). The upregulation of anti‐apoptotic Bcl‐2 members through signalling pathways within the tumor microenvironment appears as a major factor leading to resistance to venetoclax. Previously, we reported that T cells can drive resistance through CD40 and non‐canonical NF‐κB activation and subsequent Bcl‐XL induction. Moreover, the T cell‐derived cytokines IL‐21 and IL‐4 differentially affect Bcl‐XL expression and sensitivity to venetoclax via unknown mechanisms. Here, we mechanistically dissected how Bcl‐XL is regulated in the context of JAK–STAT signalling in primary CLL. First, we demonstrated a clear antagonistic role of IL‐21/STAT3 signalling in the NF‐κB‐mediated expression of Bcl‐XL, whereas IL‐4/STAT6 further promoted the expression of Bcl‐XL. In comparison, Bfl‐1, another NF‐κB target, was not differentially affected by either cytokine. Second, STAT3 and STAT6 affected Bcl‐XL transcription by binding to its promoter without disrupting the DNA‐binding activity of NF‐κB. Third, in situ proximity ligation assays (isPLAs) indicated crosstalk between JAK–STAT signalling and NF‐κB, in which STAT3 inhibited canonical NF‐κB by accelerating nuclear export, and STAT6 promoted non‐canonical NF‐κB. Finally, NF‐κB inducing kinase (NIK) inhibition interrupted the NF‐κB/STAT crosstalk and resensitized CLL cells to venetoclax. In conclusion, we uncovered distinct crosstalk mechanisms that shape the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL, thereby revealing new potential therapeutic targets.
ORCID iDs
Haselager, Marco V., Thijssen, Rachel, Bax, Danique, Both, Demi, De Boer, Francien, Mackay, Simon ORCID: https://orcid.org/0000-0001-8000-6557, Dubois, Julie, Mellink, Clemens, Kater, Arnon P. and Eldering, Eric;-
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Item type: Article ID code: 83637 Dates: DateEvent1 June 2023Published22 December 2022Published Online21 December 2022Accepted22 August 2022SubmittedSubjects: Medicine > Internal medicine > Neoplasms. Tumors. Oncology (including Cancer) Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Depositing user: Pure Administrator Date deposited: 09 Jan 2023 16:20 Last modified: 28 Oct 2024 01:46 URI: https://strathprints.strath.ac.uk/id/eprint/83637