Lachowiez Curtis A, Heiblig Mael, Aspas Requena Gaspar, Tavernier-Tardy Emmanuelle, Dai Fangyan, Ashango Amenech B, Peters Daniel T, Fang Jacob, Kaempf Andy, Long Nicola, Eide Christopher A, Kurtz Stephen E, Xie Wei, Agarwal Anupriya, Sahasrabudhe Aishwarya, McMahon Christine M, Amaya Maria L, Meyers Gabrielle, Gandhi Arpita, Leonard Jessica, Hayes-Lattin Brandon, Maziarz Richard T, Traer Elie, Cook Rachel J, Swords Ronan, Braun Theodore P, Saultz Jennifer N, Eckel Ashley M, Loken Michael R, Zeidner Joshua F, Tyner Jeffrey W, Pollyea Daniel A
Oregon Health & Science University, Portland, OR, United States.
Hospices Civils de Lyon, Oullins, France.
Blood Cancer Discov. 2025 May 21. doi: 10.1158/2643-3230.BCD-24-0256.
Resistance to venetoclax-based therapy in acute myeloid leukemia (AML) includes genetic (i.e., mutations in N/KRAS, FLT3-ITD, TP53) and phenotypic (i.e., monocytic differentiation) features. Whether monocytic differentiation contributes to clinical venetoclax resistance secondary to a genetic bias remains unknown. This multimodal, multicenter, international analysis inclusive of 678 patients comprehensively characterized the prognostic role of monocytic differentiation in AML patients treated with hypomethylating agents combined with venetoclax. AML genetics and monocytic differentiation (HR: 1.89, 95% CI: 1.35-2.66, p < 0.001) in NPM1 wild-type cases correlated with an increased risk of death. Clustering of centralized quantitative multiparameter flow cytometry data, evaluation of RNA sequencing-derived AML maturation stage, and single-cell proteogenomics linked driver mutations with AML phenotype and anti-apoptotic gene expression. This comprehensive analysis of AML genetics, phenotype, and anti-apoptotic protein expression highlights the complementary role these factors impart following venetoclax-based therapy.
急性髓系白血病（AML）对基于维奈托克的治疗产生耐药的情况包括遗传特征（即N/KRAS、FLT3-ITD、TP53中的突变）和表型特征（即单核细胞分化）。单核细胞分化是否因遗传倾向而导致临床维奈托克耐药尚不清楚。这项多模式、多中心的国际分析纳入了678例患者，全面阐述了单核细胞分化在接受去甲基化药物联合维奈托克治疗的AML患者中的预后作用。在NPM1野生型病例中，AML遗传学和单核细胞分化（风险比：1.89，95%置信区间：1.35 - 2.66，p < 0.001）与死亡风险增加相关。集中式定量多参数流式细胞术数据的聚类分析、对RNA测序得出的AML成熟阶段的评估以及单细胞蛋白质基因组学将驱动突变与AML表型和抗凋亡基因表达联系起来。对AML遗传学、表型和抗凋亡蛋白表达的全面分析突出了这些因素在基于维奈托克的治疗后所发挥的互补作用。
