Activation of c-Myc confers resistance to venetoclax via inhibition of Bim in t(8;21)-positive acute myeloid leukemia

Venetoclax (VEN), a selective BCL-2 inhibitor, has improved outcomes in acute myeloid leukemia (AML). However, patients carrying the t(8;21)(q22;q22) translocation often show limited sensitivity to VEN-based therapy. This study aimed to elucidate the molecular mechanism of VEN resistance and explore rational combination strategies. Molecular and functional analyses were performed in t(8;21) AML models to examine the role of c-Myc activation in VEN response. Pharmacologic inhibition, genetic knockdown, and xenograft studies were used to assess the effects of c-Myc and its downstream effector Bim. The efficacy of VEN combined with homoharringtonine (HHT) was further evaluated. VEN induced c-Myc expression in a dose-dependent manner, which was not suppressed by azacitidine. Inhibition or knockdown of c-Myc enhanced VEN-induced apoptosis. Mechanistically, c-Myc repressed the pro-apoptotic BH3-only protein Bim, reducing mitochondrial priming and conferring VEN resistance. HHT downregulated c-Myc and restored Bim expression, leading to synergistic anti-leukemic activity with VEN in vitro and in vivo. c-Myc activation is a key driver of VEN resistance in t(8;21) AML. HHT acts as a mechanistically complementary agent, restoring VEN sensitivity. These results provide a preclinical rationale for clinical evaluation of VEN–HHT combination therapy in genetically defined AML subsets.