Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML PMID: 42102807

ADC Targets in Oncology

2026-04-10

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

Cell Stem Cell. 2026 Jun 4;33(6):982-999.e8. doi: 10.1016/j.stem.2026.04.012.

Alexander Waclawiczek ¹ , Aino-Maija Leppä ² , Simon Renders ³ , Ines Bergerweiss ⁴ , Karolin Stumpf ⁴ , Barbara Betz ⁵ , Susanna Gabrowski ⁶ , Frank Y Huang ⁴ , Maria-Eleni Lalioti ⁷ , Bendix Hempel ² , Markus Sohn ² , Heikki Kuusanmäki ⁸ , Vera Thiel ² , Julia M Unglaub ⁹ , Rabia Shahswar ¹⁰ , Sarah Richter ⁶ , Maike Janssen ⁶ , Darja Karpova ¹¹ , Elisa Donato ² , Halvard Bonig ¹¹ , Christoph Röllig ¹² , Simon Raffel ⁶ , Michael Heuser ¹³ , Michael Hundemer ¹⁴ , Mika Kontro ⁸ , Ann-Kathrin Eisfeld ¹⁵ , Tim Sauer ⁶ , Nina Cabezas-Wallscheid ¹⁶ , Carsten Müller-Tidow ¹⁷ , Andreas Trumpp ¹⁸

Affiliations

1. Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: [email protected].
2. Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
3. Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
4. Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
5. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany; National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany.
6. Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
7. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
8. Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
9. German Cancer Consortium (DKTK), Heidelberg, Germany.
10. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
11. Institute for Transfusion Medicine and Immunohematology, Goethe University Hospital Medical School, German Red Cross Blood Donor Service, Frankfurt, Germany.
12. Medizinische Klinik und Poliklinik I, Universitätsklinikum der Technischen Universität Dresden, Dresden, Germany.
13. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; Department of Internal Medicine IV, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
14. Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; MVZ Hämatologische Diagnostik, Heppenheim, Germany.
15. Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
16. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; ETH Zürich, Department of Stem Cell Biology and Ageing, Zürich, Switzerland.
17. German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit EMBL-UKHD, Heidelberg, Germany.
18. Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: [email protected].

Abstract

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, mature monocytic/dendritic (MoDe)-LSCs, found within LAMP5⁺ 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.

Keywords

BCL-2; MAC-score; acute myeloid leukemia; azacitidine; chemotherapy; leukemic stem cells; personalized medicine; plasticity; therapy resistance; venetoclax.