1095-Stem Cell Subtypes Determine Venetoclax Resistance

This research identifies four unique leukemic stem cell (LSC) subtypes in acute myeloid leukemia that dictate how patients respond to the drug venetoclax. By profiling over 150 patients, the study reveals that therapy resistance is driven by the specific differentiation state and plasticity of these stem cells. A major finding is the discovery of MoDe-LSCs, a mature monocytic subtype identified by the marker LAMP5 that consistently resists standard treatments. The authors demonstrate that these resistant cells can be neutralized by targeting specific survival proteins, such as using MEK1/2 inhibitors for LAMP5+ cells. Ultimately, this framework provides a biomarker-guided strategy to overcome drug resistance through personalized clinical approaches. These findings suggest that subtyping LSCs can significantly improve genetic risk stratification and treatment outcomes for high-risk leukemia.

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.