I sottotipi delle cellule staminali leucemiche determinano la resistenza al venetoclax e le vulnerabilità terapeutiche nel AML.

The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling of LSCs from >150 patients, we identify four LSC subtypes. These mirror distinct hematopoietic lineage stages, which determine the expression ratio between the venetoclax target BCL-2 and resistance-inducing proteins MCL-1 and BCL-xL (MAC-score). Longitudinal analyses reveal that venetoclax resistance mostly arises in LSCs through plasticity toward a megakaryocytic/erythroid-progenitor (MEP)-LSC state that switches survival dependency from BCL-2 to BCL-xL. In rare cases, matur