Beyond BCL-2: What drives venetoclax resistance in acute myeloid leukemia?

A review in Cancer Cell synthesizes the growing understanding of venetoclax resistance mechanisms in acute myeloid leukemia, identifying compensatory shifts toward MCL-1 or BCL-xL dependence, oncogenic signaling activation, and lineage-associated blast phenotype changes as well-established pathways. Emerging but less validated mechanisms include BAX mutations, mitochondrial structural remodeling, integrated stress response activation, and metabolic adaptations such as enhanced amino acid uptake and fatty acid oxidation sustaining oxidative phosphorylation. The work provides a framework for developing rational combination strategies to overcome resistance in AML patients treated with BCL-2 inhibitors.