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. Here, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the beta subunit of the sodium-potassium pump (Na/K-ATP pump), interacts with the alpha 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 both 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. ATP1B3 is thus a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1.

中文翻译：

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以钠钾泵为靶点作为急性髓系白血病的治疗策略


旁系同源基因表达的组织特异性差异，由于伙伴对的缓冲作用，在大多数细胞类型中并不是必需的，但可以产生高度选择性的基因依赖性。为了确定急性髓系白血病 (AML) 的选择性旁系同源靶标，我们将癌症依赖性图谱与描述癌症模型中蛋白质-蛋白质相互作用、旁系同源关系和基因表达的大量数据集进行了整合。在这里，我们将 ATP1B3 确定为 AML 中上下文特定的、旁系同源相关的依赖项。 ATP1B3 是钠钾泵（Na/K-ATP 泵）的 β 亚基，与 α 亚基 ATP1A1 相互作用，形成维持所有真核细胞细胞稳态和膜电位的重要复合物。当 ATP1B3 的旁系同源物 ATP1B1 表达不良时，消除 ATP1B3 会导致 Na/K-ATP 泵不稳定。 ATP1B1 表达通过造血谱系细胞中的表观遗传沉默（通过启动子区域的组蛋白和 DNA 甲基化）进行调节。 AML 细胞中 ATP1B3 的缺失会在体外诱导细胞死亡，并减少体内的白血病负担，这可以通过 ATP1B1 的过度表达来稳定 ATP1A1 来挽救。因此，ATP1B3 是 AML 和其他 ATP1B1 低表达的血液恶性肿瘤的潜在治疗靶点。