Calcium is a ubiquitous messenger that regulates a wide range of cellular functions, but its involvement in the pathophysiology of acute myeloid leukemia (AML) is not widely investigated. Here, we identified, from an analysis of The Cancer Genome Atlas and genotype-tissue expression databases, stromal interaction molecule 2 (STIM2) as being highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients. We then investigated the role of STIM2 in cell proliferation, differentiation, and survival in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells. STIM2 expression increased at the RNA and protein levels upon monocyte differentiation. Phenotypically, STIM2 knockdown drastically inhibited cell proliferation and induced genomic stress with DNA double-strand breaks, as shown by increased levels of phosphorylate histone H2AXγ (p-H2AXγ), followed by activation of the cellular tumor antigen p53 pathway, decreased expression of cell cycle regulators such as cyclin-dependent kinase 1 (CDK1)–cyclin B1 and M-phase inducer phosphatase 3 (CDC25c), and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. Our study reports STIM2 as a new actor regulating genomic stability and p53 response in terms of cell cycle and apoptosis of human normal and malignant monocytic cells.

中文翻译：

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STIM2参与正常和恶性单核细胞的凋亡和细胞周期的调节

钙是一种普遍存在的信使，可调节多种细胞功能，但其在急性髓系白血病 (AML) 病理生理学中的作用尚未得到广泛研究。在这里，我们通过对癌症基因组图谱和基因型组织表达数据库的分析发现，基质相互作用分子 2 ( STIM2 ) 在具有单核细胞分化的 AML 中高度表达，并且与总体生存率呈负相关。这在 407 名 AML 患者的验证队列中得到了证实。然后，我们研究了 STIM2 在两种具有单核细胞潜能的白血病细胞系和正常造血干细胞中的细胞增殖、分化和存活中的作用。单核细胞分化时 STIM2 的 RNA 和蛋白质水平表达增加。表型上，STIM2敲低可显着抑制细胞增殖，并通过 DNA 双链断裂诱导基因组应激，磷酸化组蛋白 H2AXγ (p-H2AXγ) 水平增加，随后激活细胞肿瘤抗原 p53 通路，细胞周期表达减少细胞周期蛋白依赖性激酶 1 (CDK1)-细胞周期蛋白 B1 和 M 相诱导磷酸酶 3 (CDC25c) 等调节因子，以及抗凋亡/促凋亡蛋白比率降低导致的细胞凋亡阈值降低。我们的研究报告称 STIM2 作为一种新的因子，在人类正常和恶性单核细胞的细胞周期和凋亡方面调节基因组稳定性和 p53 反应。