{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T19:26:25Z","timestamp":1787858785657,"version":"build-2784847793"},"reference-count":35,"publisher":"Portland Press Ltd.","issue":"4","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015570","name":"Blood Cancer UK","doi-asserted-by":"publisher","award":["19012"],"award-info":[{"award-number":["19012"]}],"id":[{"id":"10.13039\/501100015570","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council UK","doi-asserted-by":"publisher","award":["DiMeN PhD"],"award-info":[{"award-number":["DiMeN PhD"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["DTP Precision Medicine PhD"],"award-info":[{"award-number":["DTP Precision Medicine PhD"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council, UK","doi-asserted-by":"publisher","award":["BB\/X002780\/1"],"award-info":[{"award-number":["BB\/X002780\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/T007427\/1"],"award-info":[{"award-number":["BB\/T007427\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council confidence in concept","doi-asserted-by":"publisher","award":["Confidence in Concept 309480"],"award-info":[{"award-number":["Confidence in Concept 309480"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,4,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The myeloid oncogene TRIB2 is a key driver of acute myeloid leukaemia (AML) pathogenesis, promoting chemoresistance and blocking differentiation through ubiquitin-mediated degradation of the C\/EBP\u03b1 transcription factor. Despite its stable and sometimes elevated expression across AML subtypes, TRIB2 remains a clinically untargeted vulnerability. Here, we present a comprehensive investigation into TRIB2 degradation mechanisms using multimodal approaches, including CRISPR knockout, mutational protein stability, small molecule TRIB2 engagement, and evaluation of a novel targeted protein degrader (TRIB2-PROTAC). We identify afatinib, a multi-ERBB covalent inhibitor, as a rapid inducer of TRIB2 degradation, triggering AML cell death potentially via signalling pathways distinct from ERBB. Importantly, TRIB2 degradation synergised with cytarabine, the frontline AML chemotherapy, amplifying therapeutic efficacy. Mapping of TRIB2 ubiquitination sites revealed Lys-63 as critical for its own proteolytic turnover, and a Lys-to-Arg degradation-resistant mutant (KallR) conferred enhanced chemoresistance and increased leukaemic engraftment in vivo. CRISPR-mediated TRIB2 knockout validated an essential role in AML cell survival. Consistently, the novel TRIB2-PROTAC (compound 5K) achieved robust TRIB2 degradation and AML cell killing at low micromolar concentrations. These findings establish TRIB2 as a compelling therapeutic target in AML and demonstrate that leveraging the ubiquitin-proteasome system to degrade TRIB2 offers a promising strategy to overcome chemoresistance. The present work provides strong preclinical rationale for the development of TRIB2-targeting therapies in AML.<\/jats:p>","DOI":"10.1042\/bcj20253463","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T12:23:37Z","timestamp":1773404617000},"page":"511-525","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inducing TRIB2-targeted protein degradation to reverse chemoresistance in acute myeloid leukaemia"],"prefix":"10.1042","volume":"483","author":[{"given":"Evie","family":"Rigby","sequence":"first","affiliation":[{"name":"1Wolfson Wohl Translational Cancer Research Centre, School of Cancer Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Fasanella Masci","sequence":"additional","affiliation":[{"name":"1Wolfson Wohl Translational Cancer Research Centre, School of Cancer Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshara","family":"Narayanan","sequence":"additional","affiliation":[{"name":"1Wolfson Wohl Translational Cancer Research Centre, School of Cancer Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elzbieta","family":"Kania","sequence":"additional","affiliation":[{"name":"1Wolfson Wohl Translational Cancer Research Centre, School of Cancer Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John\u00a0A.","family":"Harris","sequence":"additional","affiliation":[{"name":"2Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Williams","sequence":"additional","affiliation":[{"name":"3School of Molecular Biosciences, College of Medical, Veterinary & Life Sciences, Davidson Building, Room, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binghua","family":"Zhang","sequence":"additional","affiliation":[{"name":"3School of Molecular Biosciences, College of Medical, Veterinary & Life Sciences, Davidson Building, Room, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Liu","sequence":"additional","affiliation":[{"name":"1Wolfson Wohl Translational Cancer Research Centre, School of Cancer Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Richmond","sequence":"additional","affiliation":[{"name":"1Wolfson Wohl Translational Cancer Research Centre, School of Cancer Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengtao","family":"Zhou","sequence":"additional","affiliation":[{"name":"4International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education of People\u2019s Republic of China, College of Pharmacy, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Ding","sequence":"additional","affiliation":[{"name":"4International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education of People\u2019s Republic of China, College of Pharmacy, Jinan University, Guangzhou, China"},{"name":"5Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruaidhr\u00ed\u00a0J.","family":"Carmody","sequence":"additional","affiliation":[{"name":"3School of Molecular Biosciences, College of Medical, Veterinary & Life Sciences, Davidson Building, Room, University of Glasgow, Glasgow, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick\u00a0A.","family":"Eyers","sequence":"additional","affiliation":[{"name":"2Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7266-0890","authenticated-orcid":false,"given":"Karen","family":"Keeshan","sequence":"additional","affiliation":[{"name":"1Wolfson Wohl Translational Cancer 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