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Through <jats:italic>in vitro<\/jats:italic> studies, we observed that HDAC3 levels were elevated in BCR\u2010ABL1 kinase\u2212independent, IM\u2010resistant primary cells from CML patients and in IM\u2010resistant K562 (K562R) cells and that downregulation of HDAC3 could enhance IM efficacy in K562R cells. Furthermore, betulinic acid (BA), a lupane\u2010type pentacyclic triterpenoid saponin isolated from birch trees, restored IM sensitivity in the BCR\u2010ABL1 kinase\u2212independent, IM\u2010resistant primary cells and in K562R cells, as well as in primary CD34<jats:sup>+<\/jats:sup> bone marrow cells from CML patients. We found that BA restored IM sensitivity through inhibition of HDAC3 accumulation in cells, and that this was mediated by BA\u2010dependent ubiquitination and degradation of HDAC3. BA at low dosage significantly increased IM antitumor effects on murine xenografts bearing K562R cells and inhibited HDAC3 expression in tumor tissue. Our findings demonstrated that HDAC3 is an essential factor in BCR\u2010ABL1 kinase\u2212independent IM resistance, and that BA in combination with IM may be a novel treatment strategy for overcoming IM resistance in CML.<\/jats:p>","DOI":"10.1111\/nyas.14298","type":"journal-article","created":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T09:00:14Z","timestamp":1578906014000},"page":"77-93","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Betulinic acid restores imatinib sensitivity in BCR\u2010ABL1 kinase\u2212independent, imatinib\u2010resistant chronic myeloid leukemia by increasing HDAC3 ubiquitination and degradation"],"prefix":"10.1111","volume":"1467","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6998-5969","authenticated-orcid":false,"given":"Tingting","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Haematology Affiliated Hospital of Guizhou Medical University  Guizhou 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