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To screen drugs to overcome differentiation blockade for AML, we conducted screening of 2040 small molecules from a library of United States Food and Drug Administration\u2010approved drugs and found that the cyclin\u2010dependent kinase (CDK)4\/6 inhibitor, abemaciclib, exerts high anti\u2010leukaemic activity. Abemaciclib significantly suppressed proliferation and promoted the differentiation of LSCs in vitro. Abemaciclib also efficiently induced differentiation and impaired self\u2010renewal of LSCs, thus reducing the leukaemic cell burden and improving survival in various preclinical animal models, including patient\u2010derived xenografts. Importantly, abemaciclib strongly enhanced anti\u2010tumour effects in combination with venetoclax, a B\u2010cell lymphoma 2 (Bcl\u20102) inhibitor. This treatment combination led to a marked decrease in LSC\u2010enriched populations and resulted in a synergistic anti\u2010leukaemic effect. Target screening revealed that in addition to CDK4\/6, abemaciclib bound to and inhibited CDK9, consequently attenuating the protein levels of global p\u2010Ser2 RNA Polymerase II (Pol II) carboxy terminal domain (CTD), Myc, Bcl\u20102, and myeloid cell leukaemia\u20101 (Mcl\u20101), which was important for the anti\u2010AML effect of abemaciclib. Collectively, these data provide a strong rationale for the clinical evaluation of abemaciclib to induce LSC differentiation and treat highly aggressive AML as well as other advanced haematological malignancies.<\/jats:p>","DOI":"10.1111\/bjh.18735","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T08:17:48Z","timestamp":1678781868000},"page":"940-953","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Abemaciclib drives the therapeutic differentiation of acute myeloid leukaemia stem cells"],"prefix":"10.1111","volume":"201","author":[{"given":"Xiaoling","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Hematology Zhujiang Hospital, Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuju","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology The Fifth Affiliated 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