Curtis A Lachowiez, Mael Heiblig, Gaspar Aspas Requena, Emmanuelle Tavernier-Tardy, Fangyan Dai, Amenech B Ashango, Daniel T Peters, Jacob Fang, Andy Kaempf, Nicola Long, Christopher A Eide, Stephen E Kurtz, Wei Xie, Anupriya Agarwal, Aishwarya Sahasrabudhe, Christine M McMahon, Maria L Amaya, Gabrielle Meyers, Arpita Gandhi, Jessica Leonard, Brandon Hayes-Lattin, Richard T Maziarz, Elie Traer, Rachel J Cook, Ronan Swords, Theodore P Braun, Jennifer N Saultz, Ashley M Eckel, Michael R Loken, Joshua F Zeidner, Jeffrey W Tyner, Daniel A Pollyea
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引用次数: 0
摘要
急性髓性白血病（AML）对venetoclax为基础的治疗的耐药性包括遗传（即N/KRAS， FLT3-ITD， TP53的突变）和表型（即单核细胞分化）特征。是否单核细胞分化有助于继发于遗传偏倚的临床venetoclax耐药仍然未知。这项多模式、多中心、包括678例患者的国际分析全面表征了单核细胞分化在接受低甲基化药物联合venetoclax治疗的AML患者中的预后作用。NPM1野生型病例的AML遗传和单核细胞分化（HR: 1.89, 95% CI: 1.35-2.66, p < 0.001）与死亡风险增加相关。集中定量多参数流式细胞术数据的聚类，RNA测序衍生的AML成熟阶段的评估，以及与AML表型和抗凋亡基因表达相关的驱动突变的单细胞蛋白质基因组学。这项对AML遗传学、表型和抗凋亡蛋白表达的综合分析强调了这些因素在venetoclax为基础的治疗后所具有的互补作用。
Genetic and Phenotypic correlates of clinical outcomes with Venetoclax in Acute Myeloid Leukemia: The GEN-PHEN-VEN study.
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.
期刊介绍：
The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes.
The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence.
Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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