JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL
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 lead...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-06-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13364 |
| _version_ | 1797807031278632960 |
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| author | Marco V. Haselager Rachel Thijssen Danique Bax Demi Both Francien De Boer Simon Mackay Julie Dubois Clemens Mellink Arnon P. Kater Eric Eldering |
| author_facet | Marco V. Haselager Rachel Thijssen Danique Bax Demi Both Francien De Boer Simon Mackay Julie Dubois Clemens Mellink Arnon P. Kater Eric Eldering |
| author_sort | Marco V. Haselager |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T06:16:24Z |
| format | Article |
| id | doaj.art-2e43009de0ac4b10a008f5313a882ab0 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-13T06:16:24Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-2e43009de0ac4b10a008f5313a882ab02023-06-10T14:59:12ZengWileyMolecular Oncology1574-78911878-02612023-06-011761112112810.1002/1878-0261.13364JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XLMarco V. Haselager0Rachel Thijssen1Danique Bax2Demi Both3Francien De Boer4Simon Mackay5Julie Dubois6Clemens Mellink7Arnon P. Kater8Eric Eldering9Department of Experimental Immunology Amsterdam UMC location University of Amsterdam The NetherlandsDepartment of Experimental Immunology Amsterdam UMC location University of Amsterdam The NetherlandsDepartment of Experimental Immunology Amsterdam UMC location University of Amsterdam The NetherlandsDepartment of Experimental Immunology Amsterdam UMC location University of Amsterdam The NetherlandsIkazia Ziekenhuis Rotterdam The NetherlandsStrathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde Glasgow UKDepartment of Hematology Amsterdam UMC location University of Amsterdam The NetherlandsDepartment of Clinical Genetics Amsterdam UMC location University of Amsterdam The NetherlandsAmsterdam institute for Infection & Immunity The NetherlandsDepartment of Experimental Immunology Amsterdam UMC location University of Amsterdam The NetherlandsPreventing 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.https://doi.org/10.1002/1878-0261.13364chronic lymphocytic leukaemiadrug resistancemicroenvironmentsignalling |
| spellingShingle | Marco V. Haselager Rachel Thijssen Danique Bax Demi Both Francien De Boer Simon Mackay Julie Dubois Clemens Mellink Arnon P. Kater Eric Eldering JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL Molecular Oncology chronic lymphocytic leukaemia drug resistance microenvironment signalling |
| title | JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL |
| title_full | JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL |
| title_fullStr | JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL |
| title_full_unstemmed | JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL |
| title_short | JAK–STAT signalling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL |
| title_sort | jak stat signalling shapes the nf κb response in cll towards venetoclax sensitivity or resistance via bcl xl |
| topic | chronic lymphocytic leukaemia drug resistance microenvironment signalling |
| url | https://doi.org/10.1002/1878-0261.13364 |
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