Preclinical work shows that combining the BCL‑2 inhibitor venetoclax with the FLT3 inhibitor gilteritinib produces deep, reproducible anti‑leukemia activity in FLT3‑mutant, BCL11B‑activated lineage‑ambiguous leukemias. BH3 profiling and single‑cell transcriptomics reveal mechanisms of resistance and biology of residual cells, supporting rapid clinical evaluation.