Karakaslar E Onur, Severens Jeppe F, Sánchez-López Elena, van Veelen Peter A, Zlei Mihaela, van Dongen Jacques J M, Otte Annemarie M, Halkes Constantijn J M, van Balen Peter, Veelken Hendrik, Reinders Marcel J T, Griffioen Marieke, van den Akker Erik B
Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Pattern Recognition & Bioinformatics, Delft University of Technology, Delft, The Netherlands.
NPJ Precis Oncol. 2024 May 18;8(1):105. doi: 10.1038/s41698-024-00596-9.
The diagnostic spectrum for AML patients is increasingly based on genetic abnormalities due to their prognostic and predictive value. However, information on the AML blast phenotype regarding their maturational arrest has started to regain importance due to its predictive power for drug responses. Here, we deconvolute 1350 bulk RNA-seq samples from five independent AML cohorts on a single-cell healthy BM reference and demonstrate that the morphological differentiation stages (FAB) could be faithfully reconstituted using estimated cell compositions (ECCs). Moreover, we show that the ECCs reliably predict ex-vivo drug resistances as demonstrated for Venetoclax, a BCL-2 inhibitor, resistance specifically in AML with CD14+ monocyte phenotype. We validate these predictions using LUMC proteomics data by showing that BCL-2 protein abundance is split into two distinct clusters for NPM1-mutated AML at the extremes of CD14+ monocyte percentages, which could be crucial for the Venetoclax dosing patients. Our results suggest that Venetoclax resistance predictions can also be extended to AML without recurrent genetic abnormalities and possibly to MDS-related and secondary AML. Lastly, we show that CD14+ monocytic dominated Ven/Aza treated patients have significantly lower overall survival. Collectively, we propose a framework for allowing a joint mutation and maturation stage modeling that could be used as a blueprint for testing sensitivity for new agents across the various subtypes of AML.
由于基因异常具有预后和预测价值，急性髓系白血病（AML）患者的诊断范围越来越多地基于这些异常情况。然而，AML原始细胞表型关于其成熟停滞的信息，因其对药物反应的预测能力而重新开始受到重视。在此，我们在单细胞健康骨髓参考样本上对来自五个独立AML队列的1350个批量RNA测序样本进行解卷积分析，结果表明，使用估计的细胞组成（ECC）能够准确地重建形态学分化阶段（FAB）。此外，我们还表明，ECC能够可靠地预测体外药物抗性，如针对BCL-2抑制剂维奈托克的抗性，特别是在具有CD14+单核细胞表型的AML中。我们通过LUMC蛋白质组学数据验证了这些预测，结果显示，在CD14+单核细胞百分比的极端情况下，对于NPM1突变的AML，BCL-2蛋白丰度分为两个不同的簇，这对于维奈托克给药患者可能至关重要。我们的结果表明，维奈托克抗性预测也可以扩展到没有复发性基因异常的AML，甚至可能扩展到与骨髓增生异常综合征（MDS）相关的和继发性AML。最后，我们表明，CD14+单核细胞占主导的维奈托克/阿扎胞苷治疗患者的总生存期显著更低。总体而言，我们提出了一个框架，允许进行联合突变和成熟阶段建模，该框架可作为测试新药物对AML各种亚型敏感性的蓝图。
