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The standard of care remains to be chemotherapy and stem cell transplantation. In acute promyelocytic leukaemia (APL), differentiation therapy with all\u2010trans retinoic acid (ATRA) has significantly improved outcomes. Despite this, the success of ATRA has yet to be transferred to non\u2010APL AML. Exploring combinations to enhance the efficacy of ATRA in non\u2010APL AML remains a key focus. To investigate the therapeutic effect of ATRA in combination with cyclin\u2010dependent kinase 4\/6 (CDK4\/6) inhibitors in non\u2010APL AML. Non\u2010APL AML cell lines and primary patient samples were treated with ATRA and CDK4\/6 inhibitors. Key outcomes included differentiation, proliferation, cell viability and colony\u2010forming capacity. Combination synergy was evaluated, and gene expression analysis identified pathways associated with therapeutic effects. The combination demonstrated dose\u2010dependent effects, enhancing differentiation and reducing proliferation, cell viability and colony\u2010forming capacity. A synergistic effect was observed across AML cell lines. Gene expression profiling revealed the co\u2010regulation of differentiation\u2010associated genes, unveiling the mechanisms driving therapeutic synergy. Combination of CDK4\/6 inhibitors with ATRA shows potential for differentiation\u2010based AML treatment. This approach offers a promising avenue for improved outcomes in non\u2010APL AML.<\/jats:p>","DOI":"10.1111\/bjh.70057","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T09:00:41Z","timestamp":1754298041000},"page":"1279-1288","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Synergistic potential of <scp>CDK4<\/scp>\/6 inhibitors and <scp>ATRA<\/scp> in non\u2010<scp>APL AML<\/scp>"],"prefix":"10.1111","volume":"207","author":[{"given":"Rafa\u0142","family":"Skopek","sequence":"first","affiliation":[{"name":"Department of Molecular Biology Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences  Magdalenka Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3169-6880","authenticated-orcid":false,"given":"Setenay Gupse","family":"\u00d6zcan","sequence":"additional","affiliation":[{"name":"Department of 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