Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML

Alexander Waclawiczek; Aino‐Maija Leppä; Simon Renders; Ines Bergerweiss; Karolin Stumpf; Barbara Betz; Susanna Gabrowski; Frank Y. Huang; Maria‐Eleni Lalioti; Bendix Hempel; Markus Sohn; Heikki Kuusanmäki; Vera Thiel; Julia M. Unglaub; Rabia Shahswar; Sarah Richter; Maike Janssen; Darja Karpova; Elisa Donato; Halvard Bonig; Christoph Röllig; Simon Raffel; Michael Heuser; Michael Hundemer; Mika Kontro; Ann-Kathrin Eisfeld; Tim Sauer; Nina Cabezas‐Wallscheid; Carsten Müller-Tidow; Andreas Trumpp

doi:10.1016/j.stem.2026.04.012

Key Points

This research aims to identify leukemic stem cell subtypes that contribute to venetoclax resistance in AML and explore potential targeted therapies.
Subtyped leukemic stem cells to assess resistance mechanisms to venetoclax.
Evaluated responses of specific LSC types to various therapeutic agents such as BCL-xL and MEK1/2 inhibitors.
Identified four distinct LSC types with unique vulnerabilities.
MEP-LSCs showed resistance to venetoclax but responsiveness to BCL-xL inhibitors.
MoDe-LSCs were sensitive to MEK1/2 inhibition.

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Implication

Investigates venetoclax resistance in AML, suggesting targeted therapies for effective treatment.

Abstract

monocytic AMLs, drive venetoclax resistance. LSC subtyping improves genetic risk stratification and provides subtype-specific therapies: venetoclax-resistant MEP-LSCs respond to BCL-xL inhibitors, whereas MoDe-LSCs are sensitive to MEK1/2 inhibition. Our findings reveal four distinct LSC types with unique vulnerabilities and propose biomarker-guided treatment strategies that complement genetic profiling to overcome venetoclax resistance.

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Cite This Study

Waclawiczek et al. (2026) studied this question.

synapsesocial.com/papers/6a0171473a9f334c282718fd https://doi.org/10.1016/j.stem.2026.04.012

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Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML

Key Points

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Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML

Key Points

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Abstract

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