Highly multiplexed proteomic assessment of human bone marrow in acute myeloid leukemia
Highly multiplexed proteomic assessment of human bone marrow in acute myeloid leukemia
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DOI：
10.1182/bloodadvances.2019001124
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发表时间：
2020-01-28
期刊：
影响因子：
7.5
通讯作者：
Hourigan, Christopher S.
中科院分区：
文献类型：
--
作者：
Celik, Haydar;Lindblad, Katherine E.;Hourigan, Christopher S.
急性髓性白血病（AML）是一种遗传异质性疾病，其特征在于主要在骨髓（BM）和血液中发现的髓样祖细胞的异常克隆增殖。最近的研究表明，BM微环境中的遗传和表型改变支持白血病发生，并允许白血病细胞存活并逃避化疗诱导的死亡。然而，尽管有大量证据表明肿瘤-宿主相互作用在AML发病机制中的作用，但对BM的复杂微环境知之甚少。为了解决这个问题，我们使用基于适体的高度多重亲和蛋白质组学平台（SOMAscan）对AML患者（n = 10）和年龄和性别匹配的健康对照受试者（n = 10）的BM微环境的非细胞区室进行了新的蛋白质组学分析。我们表明，血液蛋白质组学评估或骨髓RNA测序是次优的替代筛选策略，以确定AML患者骨髓细胞外可溶性隔室的真正蛋白质组组成。蛋白质组学分析显示，168个蛋白质在丰度上显著不同，其中91个在白血病BM中上调，77个下调。发现细胞因子和趋化因子（包括IL-8）的高度连接的信号传导网络是BM微环境中与AML相关的最突出的蛋白质组特征。我们首次报道了AML和骨髓增生异常综合征患者骨髓抑制趋化因子CCL 23（髓系祖细胞抑制因子-1）水平显著升高，并进行了支持正常造血抑制作用的功能实验。这个独特的配对RNA测序和蛋白质组学数据集为AML和健康老龄化提供了创新的机制见解，应该作为一个有用的公共资源。
Acute myeloid leukemia (AML) is a genetically heterogeneous disease that is characterized by abnormal clonal proliferation of myeloid progenitor cells found predominantly within the bone marrow (BM) and blood. Recent studies suggest that genetic and phenotypic alterations in the BM microenvironment support leukemogenesis and allow leukemic cells to survive and evade chemotherapy -induced death. However, despite substantial evidence indicating the role of tumor -host interactions in AML pathogenesis, little is known about the complex microenvironment of the BM. To address this, we performed novel proteomic profiling of the noncellular compartment of the BM microenvironment in patients with AML (n - 10) and age- and sex -matched healthy control subjects (n = 10) using an aptamer-based, highly multiplexed, affinity proteomics platform (SOMAscan). We show that proteomic assessment of blood or RNA-sequencing of BM are suboptimal alternate screening strategies to determine the true proteomic composition of the extracellular soluble compartment of AML patient BM. Proteomic analysis revealed that 168 proteins significantly differed in abundance, with 91 upregulated and 77 downregulated in leukemic BM. A highly connected signaling network of cytokines and chemokines, including IL-8, was found to be the most prominent proteomic signature associated with AML in the BM microenvironment. We report the first description of significantly elevated levels of the myelosuppressive chemokine CCL23 (myeloid progenitor inhibitory factor-1) in both AML and myelodysplastic syndrome patients and perform functional experiments supportive of a role in the suppression of normal hematopoiesis. This unique paired RNA-sequencing and proteomics data set provides innovative mechanistic insights into AML and healthy aging and should serve as a useful public resource.