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The prognosis for AML is therefore poor, and there is an urgent need for new treatments for this condition. Gemtuzumab ozogamicin (GO), the first antibody\u2010drug conjugate (ADC), targets the CD33 antigen expressed in over 90% of AML cases. GO therefore has the potential to counter the heterogeneity of AML patients. However, a major clinical problem is that drug resistance to GO diminishes its effect over time. Here, we report that the inhibition of glycogen synthase kinase 3 (GSK3) alone overcomes several forms of GO resistance at concentrations without antileukemic effects. The GSK3 inhibitors tested significantly enhanced the cytotoxic effect of GO in AML cell lines. We elucidated four mechanisms of enhancement: (1) increased expression of CD33, the target antigen of GO; (2) activation of a lysosomal function essential for hydrolysis of the GO linker; (3) reduced expression of MDR1 that eliminates calicheamicin, the payload of GO; and (4) reduced expression of the anti\u2010apoptotic factor Bcl\u20102. A similar combination effect was observed against patient\u2010derived primary AML cells. Combining GO with GSK3 inhibitors may be efficacious in treating heterogeneous AML.<\/jats:p>","DOI":"10.1002\/jha2.600","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T06:14:00Z","timestamp":1670912040000},"page":"153-164","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["GSK3 inhibitor enhances gemtuzumab ozogamicin\u2010induced apoptosis in primary human leukemia cells by overcoming multiple mechanisms of resistance"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6718-3433","authenticated-orcid":false,"given":"Aki","family":"Inase","sequence":"first","affiliation":[{"name":"Division of Bioresource Research and Development Department of Social\/Community Medicine and Health Science Kobe University Graduate School of Medicine  Kobe Japan"},{"name":"Division of Medical Oncology and Hematology Department of Medicine Kobe University Graduate 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