Several studies including ours demonstrate that AML1/ETO-positive acute myeloid leukemia (AML) has poor response to venetoclax (Ven) combined with azacitidine (AZA). Besides, our study showed the addition of homoharringtonine (HHT) to Ven/AZA significantly improved response. Recent studies revealed AML1/ETO could activate fatty acid metabolism (FAM) in leukemia stem cells (LSCs). FAM is a critical factor to Ven/AZA resistance. All these findings indicate that Ven/AZA resistance in AML1/ETO-positive AML might be associated with activation of FAM. However, how FAM is activated and why HHT could onvercome the resistance remai unclear. In this study, we did observe significantly activated FAM in AML1/ETO-positive AML cells compared to the negative ones. Ven resulted in a dose-dependent increase in c-Myc and Stearoyl-CoA Desaturase-1 (SCD1) expression, which was inhibited by HHT but not AZA, in AML1/ETO-positive cell lines and primary cells. Pharmacologic inhibition or genetic knockdown of c-Myc or SCD1 enhanced the anti-leukemia effect of Ven, while up-regulation of c-Myc or SCD1 did the opposite. C-Myc directly regulated the transcription and translation of SCD1, and then impacted on the uptake, de novo synthesis and OPHOXS of fatty acid (FA). In vitro and in vivo experiments demonstrated that HHT significantly enhanced the anti-leukemia effect of Ven via inhibition of c-Myc/SCD1 pathway, and the enhancing effect was counteracted by adding FA. Altogether, our study highlighted an innorvative mechanism of FAM-mediated Ven resistance in AML1/ETO-positive AML and demostrated a promising strategy of adding HHT to overcome the resistance.

Key words: AML1/ETO, fatty acid metabolism, c-Myc, SCD1, venetoclax

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2025
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