Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Tomtebodavägen 23A, 171 65, Solna, Sweden.
Institute of Plant Biology and Biotechnology, University of Muenster, Schlossplatz 7, 48149, Muenster, Germany.
Nat Commun. 2022 Mar 30;13(1):1691. doi: 10.1038/s41467-022-29224-5.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although standard-of-care chemotherapeutics are sufficient for most ALL cases, there are subsets of patients with poor response who relapse in disease. The biology underlying differences between subtypes and their response to therapy has only partially been explained by genetic and transcriptomic profiling. Here, we perform comprehensive multi-omic analyses of 49 readily available childhood ALL cell lines, using proteomics, transcriptomics, and pharmacoproteomic characterization. We connect the molecular phenotypes with drug responses to 528 oncology drugs, identifying drug correlations as well as lineage-dependent correlations. We also identify the diacylglycerol-analog bryostatin-1 as a therapeutic candidate in the MEF2D-HNRNPUL1 fusion high-risk subtype, for which this drug activates pro-apoptotic ERK signaling associated with molecular mediators of pre-B cell negative selection. Our data is the foundation for the interactive online Functional Omics Resource of ALL (FORALL) with navigable proteomics, transcriptomics, and drug sensitivity profiles at https://proteomics.se/forall .
急性淋巴细胞白血病（ALL）是最常见的儿童癌症。尽管标准的化疗药物对于大多数 ALL 病例是足够的，但仍有一部分患者对治疗反应不佳，疾病会复发。遗传和转录组分析只能部分解释亚型之间的生物学差异及其对治疗的反应。在这里，我们使用蛋白质组学、转录组学和药物蛋白质组学特征分析，对 49 种易得的儿童 ALL 细胞系进行了全面的多组学分析。我们将分子表型与 528 种肿瘤药物的反应联系起来，确定了药物相关性以及谱系依赖性相关性。我们还确定了二酰基甘油类似物 bryostatin-1 是 MEF2D-HNRNPUL1 融合高危亚型的治疗候选药物，这种药物激活了与 pre-B 细胞负选择的分子介质相关的促凋亡 ERK 信号。我们的数据是 ALL 在线交互式功能组学资源（FORALL）的基础，该资源具有可导航的蛋白质组学、转录组学和药物敏感性谱，网址为 https://proteomics.se/forall。
