1049-LSC Subtypes Driving Venetoclax Resistance in AML

This research identifies four distinct subtypes of leukemic stem cells (LSCs) in acute myeloid leukemia that dictate how patients respond to the drug venetoclax. By profiling over 150 patients, the authors discovered that resistance often stems from LSC plasticity, where cells shift into a megakaryocytic/erythroid state or exist as a rare LAMP5+ monocytic/dendritic (MoDe) subtype. These specific cellular states allow the cancer to bypass BCL-2 inhibition by relying on alternative survival proteins like MCL-1 or BCL-xL. Crucially, the study demonstrates that these resistant LSCs possess unique therapeutic vulnerabilities that can be neutralized using MEK1/2 or BCL-xL inhibitors. This framework offers a biomarker-guided strategy to improve genetic risk assessment and personalize treatments for refractory leukemia. Utilizing surface markers like LAMP5 allows clinicians to quickly identify high-risk patients and deploy more effective, subtype-specific drug combinations.

References:

• Waclawiczek A, Leppä A M, Renders S, et al. Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML[J]. Cell Stem Cell, 2026.