{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:15:46Z","timestamp":1786976146584,"version":"build-2736575974"},"reference-count":56,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T00:00:00Z","timestamp":1676246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:p>\n                    Preventing or overcoming resistance to the Bcl\u20102 inhibitor venetoclax is an emerging unmet clinical need in patients with chronic lymphocytic leukaemia (CLL). The upregulation of anti\u2010apoptotic Bcl\u20102 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\u2010canonical NF\u2010\u03baB activation and subsequent Bcl\u2010XL induction. Moreover, the T cell\u2010derived cytokines IL\u201021 and IL\u20104 differentially affect Bcl\u2010XL expression and sensitivity to venetoclax via unknown mechanisms. Here, we mechanistically dissected how Bcl\u2010XL is regulated in the context of JAK\u2013STAT signalling in primary CLL. First, we demonstrated a clear antagonistic role of IL\u201021\/STAT3 signalling in the NF\u2010\u03baB\u2010mediated expression of Bcl\u2010XL, whereas IL\u20104\/STAT6 further promoted the expression of Bcl\u2010XL. In comparison, Bfl\u20101, another NF\u2010\u03baB target, was not differentially affected by either cytokine. Second, STAT3 and STAT6 affected Bcl\u2010XL transcription by binding to its promoter without disrupting the DNA\u2010binding activity of NF\u2010\u03baB. Third,\n                    <jats:italic>in\u2009situ<\/jats:italic>\n                    proximity ligation assays (isPLAs) indicated crosstalk between JAK\u2013STAT signalling and NF\u2010\u03baB, in which STAT3 inhibited canonical NF\u2010\u03baB by accelerating nuclear export, and STAT6 promoted non\u2010canonical NF\u2010\u03baB. Finally, NF\u2010\u03baB inducing kinase (NIK) inhibition interrupted the NF\u2010\u03baB\/STAT crosstalk and resensitized CLL cells to venetoclax. In conclusion, we uncovered distinct crosstalk mechanisms that shape the NF\u2010\u03baB response in CLL towards venetoclax sensitivity or resistance via Bcl\u2010XL, thereby revealing new potential therapeutic targets.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13364","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:50:34Z","timestamp":1671756634000},"page":"1112-1128","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["<scp>JAK\u2013STAT<\/scp>\n                    signalling shapes the\n                    <scp>NF\u2010\u03baB<\/scp>\n                    response in\n                    <scp>CLL<\/scp>\n                    towards venetoclax sensitivity or resistance via\n                    <scp>Bcl\u2010XL<\/scp>"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1410-7285","authenticated-orcid":false,"given":"Marco 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Mackay","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Dubois","sequence":"additional","affiliation":[{"name":"Department of Hematology Amsterdam UMC location University of Amsterdam  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Mellink","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Amsterdam UMC location University of Amsterdam  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnon P.","family":"Kater","sequence":"additional","affiliation":[{"name":"Amsterdam institute for Infection &amp; Immunity  The Netherlands"},{"name":"Cancer Immunology Cancer Center Amsterdam  The 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