However, the molecular landscape of this resistance remains insufficiently understood.<h4>Methods</h4>To address this, we developed venetoclax-resistant AML cell models and utilized transcriptomic profiling integrated with comprehensive in vitro and in vivo functional assays.<h4>Results</h4>Resistant cells demonstrated sustained proliferation even under the suppression of BCL-2, MCL-1, and key intrinsic apoptotic markers, including cleaved PARP and caspase-9, indicating a bypass mechanism independent of classical BCL-2 signaling. Here, CASP9 is linked to acute myeloid leukemia.