Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated acute myeloid leukemia (AML) patients. However, upfront resistance as well as relapse following initial response demonstrate the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax + azacitidine in AML patients correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptome profile, loses expression of venetoclax target BCL2 and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis.

中文翻译：

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单核细胞亚克隆使急性髓系白血病患者对基于维奈托克的治疗产生耐药性。


基于 Venetoclax 的治疗可以在约 70% 的先前未经治疗的老年急性髓系白血病 (AML) 患者中产生缓解。然而，前期耐药性以及初始反应后的复发表明需要更深入地了解耐药机制。在本研究中，我们报告说，AML 患者对维奈托克 + 阿扎胞苷的反应与发育阶段密切相关，其中表型原始 AML 较敏感，但单核细胞 AML 更具耐药性。从机制上讲，耐药性单核细胞 AML 具有独特的转录组特征，失去 Venetoclax 靶标 BCL2 的表达，并依赖 MCL1 介导氧化磷酸化和生存。这种不同的敏感性驱动了患者的选择性过程，有利于复发时单核细胞亚群的生长。基于这些发现，我们得出结论，由于单核细胞分化固有的生物学特性，可能会产生对维奈托克+阿扎胞苷的耐药性。我们建议设计最佳的 AML 疗法，以独立针对可能在发病不同阶段出现的 AML 亚克隆。