We are delighted to congratulate several CRC1709 researchers on their contribution to a new publication in Cell Stem Cell:
Waclawiczek, A., Leppä, A.-M., Renders, S. et al. Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML. Cell Stem Cell (2026).
The study, led by researchers from the Trumpp Lab (PI, A05) at HI-STEM and DKFZ, addresses one of the major clinical challenges in acute myeloid leukemia (AML): why patients relapse despite treatment with the BCL-2 inhibitor venetoclax.
Importantly, several CRC1709 Principal Investigators contributed to this collaborative effort, including Carsten Müller-Tidow, Simon Raffel, Maike Janssen, and Tim Sauer.
Four leukemic stem cell states shape treatment response
By analysing leukemic stem cells (LSCs) from more than 150 AML patients, the researchers identified four distinct LSC subtypes that mirror different stages of blood cell development. These cellular states determine how leukemia stem cells respond to therapy.
The study demonstrates that resistance to venetoclax is not random but strongly linked to the differentiation state and plasticity of leukemic stem cells. While some LSC subtypes remain sensitive to BCL-2 inhibition, others adapt by switching to alternative survival mechanisms.
Plasticity as a driver of therapy resistance
One of the key findings is that leukemic stem cells can transition into a megakaryocytic/erythroid progenitor-like state, thereby changing their dependency from BCL-2 to BCL-xL and escaping venetoclax treatment. In another subset of AML, mature monocytic/dendritic LSCs rely on distinct signalling pathways that may be targeted through MEK1/2 inhibition.
These findings highlight how cellular plasticity contributes directly to therapeutic resistance and disease progression.
Towards more precise therapies
Beyond improving our understanding of AML biology, the work provides a framework for biomarker-guided treatment strategies. The authors propose that identifying the underlying LSC subtype may help clinicians select more effective therapies tailored to individual patients and overcome treatment resistance.
The study represents an outstanding example of interdisciplinary collaboration and illustrates how fundamental discoveries in cell plasticity can pave the way for future precision medicine approaches.
Congratulations to all researchers involved in this remarkable achievement.
Reference
Waclawiczek A, Leppä A-M, Renders S, et al. Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML. Cell Stem Cell. 2026;33(6):982–999.e8. DOI: 10.1016/j.stem.2026.04.012.
