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

IF 20.4

Cell stem cell Pub Date : 2026-06-04 Epub Date: 2026-05-07 DOI:10.1016/j.stem.2026.04.012

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

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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.

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白血病干细胞亚型决定急性髓性白血病（AML）的venetoclax耐药性和治疗脆弱性。

BCL-2抑制剂venetoclax已经改变了急性髓性白血病（AML）的治疗，但由于白血病干细胞（LSCs）的耐药而复发仍然是一个主要挑战。通过对bbb150例患者LSC的分子和功能分析，我们确定了4种LSC亚型。这些反映了不同的造血谱系阶段，决定了venetoclax靶点BCL-2和耐药诱导蛋白MCL-1和BCL-xL （MAC-score）之间的表达比例。纵向分析显示，venetoclax耐药主要发生在LSCs中，通过向巨核细胞/红细胞祖细胞(MEP)-LSC状态的可塑性，将生存依赖从BCL-2转换为BCL-xL。在极少数情况下，在LAMP5+单核AMLs中发现的成熟单核/树突状(MoDe)-LSCs驱动venetoclax抗性。LSC亚型可以改善遗传风险分层，并提供亚型特异性治疗：venetoclax耐药的MEP-LSCs对BCL-xL抑制剂有反应，而MoDe-LSCs对MEK1/2抑制剂敏感。我们的研究结果揭示了四种不同的LSC类型具有独特的脆弱性，并提出了生物标志物引导的治疗策略，以补充遗传谱来克服venetoclax耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Cell stem cell

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