Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia.

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-10-15 DOI:10.1158/0008-5472.CAN-23-3560
Constanze Schneider, Hermes Spaink, Gabriela Alexe, Neekesh V Dharia, Ashleigh Meyer, Lucy A Merickel, Delan Khalid, Sebastian Scheich, Björn Häupl, Louis M Staudt, Thomas Oellerich, Kimberly Stegmaier
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Abstract

Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein-protein interactions, paralog relationships, and gene expression in cancer models. In this study, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the β-subunit of the sodium-potassium pump (Na/K-ATP pump), interacts with the α-subunit ATP1A1 to form an essential complex for maintaining cellular homeostasis and membrane potential in all eukaryotic cells. When ATP1B3's paralog ATP1B1 is poorly expressed, elimination of ATP1B3 leads to the destabilization of the Na/K-ATP pump. ATP1B1 expression is regulated through epigenetic silencing in hematopoietic lineage cells through histone and DNA methylation in the promoter region. Loss of ATP1B3 in AML cells induced cell death in vitro and reduced leukemia burden in vivo, which could be rescued by stabilizing ATP1A1 through overexpression of ATP1B1. Thus, ATP1B3 is a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1. Significance: ATP1B3 is a lethal selective paralog dependency in acute myeloid leukemia that can be eliminated to destabilize the sodium-potassium pump, inducing cell death.

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靶向钠钾泵作为急性髓性白血病的治疗策略
在大多数细胞类型中,旁系基因的表达存在组织特异性差异,但由于配对伙伴的缓冲作用,这些旁系基因的表达并不是必需的,这可能会产生高度选择性的基因依赖关系。为了确定急性髓性白血病(AML)的选择性旁系靶标,我们将癌症依赖性图谱与表征蛋白质-蛋白质相互作用、旁系亲属关系和癌症模型中基因表达的大量数据集进行了整合。在这里,我们确定了 ATP1B3 在急性髓细胞白血病中的上下文特异性、旁系亲属关系。ATP1B3是钠-钾泵(Na/K-ATP泵)的β亚基,它与α亚基ATP1A1相互作用,形成维持细胞平衡和所有真核细胞膜电位的重要复合物。当 ATP1B3 的同系物 ATP1B1 表达低下时,消除 ATP1B3 会导致 Na/K-ATP 泵不稳定。ATP1B1 的表达在造血系细胞中通过启动子区域的组蛋白和 DNA 甲基化进行表观遗传沉默调节。急性髓细胞中 ATP1B3 的缺失在体外诱导细胞死亡,在体内减少白血病的负担,这可以通过过表达 ATP1B1 稳定 ATP1A1 来挽救。因此,ATP1B3 是急性髓细胞性白血病和其他 ATP1B1 低表达血液恶性肿瘤的潜在治疗靶点。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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