NPM1c impedes CTCF functions through cytoplasmic mislocalization in acute myeloid leukemia.,Leukemia

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NPM1c impedes CTCF functions through cytoplasmic mislocalization in acute myeloid leukemia.
Leukemia ( IF 12.8 ) Pub Date : 2019-12-12 , DOI: 10.1038/s41375-019-0681-8
Atom J Wang _{1,

2} , Youqi Han ₁ , Nanyang Jia ₃ , Peikun Chen ₃ , Mark D Minden _{1,

2}

Affiliation

Normal cytogenetic acute myeloid leukemia (AML) frequently harbor a TCTG insertion in exon 12 of Nucleophosmin 1 (NPM1); the resulting frameshift creates a nuclear export signal (NES) and cytoplasmic localization of NPM1c. However, how NPM1c causes AML is not completely understood. NPM1 participates in multiple protein-protein interactions one of which involves the CCCTC-binding factor (CTCF). Through binding of CTCF binding sites (CBS), CTCF mediates nuclear functions including DNA looping, regulation of gene expression, and RNA splicing. We hypothesized that mislocalization of CTCF into the cytoplasm by NPM1c reduces the functional level of nuclear CTCF and so alters gene expression. We verified the interaction of CTCF with NPM1 and showed that CTCF interacts with NPM1c, with redistribution of CTCF into the cytoplasm. The interaction of CTCF and NPM1c involves the amino terminus of CTCF and the last 50 amino acids of NPM1. By interfering with the interaction of CTCF and NPM1c, CTCF becomes relocalized into the nucleus.

中文翻译：

NPM1c通过急性髓性白血病中的胞质错位阻碍CTCF的功能。

正常的细胞遗传性急性髓细胞性白血病（AML）经常在核蛋白1（NPM1）外显子12的TCTG插入；由此产生的移码会产生核输出信号（NES）和NPM1c的胞质定位。但是，尚未完全了解NPM1c如何导致AML。NPM1参与多种蛋白质-蛋白质相互作用，其中之一涉及CCCTC结合因子（CTCF）。通过结合CTCF结合位点（CBS），CTCF介导核功能，包括DNA环化，基因表达调控和RNA剪接。我们假设NPM1c将CTCF误定位到细胞质中会降低核CTCF的功能水平，从而改变基因表达。我们验证了CTCF与NPM1的相互作用，并表明CTCF与NPM1c相互作用，并且CTCF重新分布到细胞质中。CTCF和NPM1c的相互作用涉及CTCF的氨基末端和NPM1的后50个氨基酸。通过干扰CTCF和NPM1c的相互作用，CTCF重新定位到细胞核中。

更新日期：2019-12-13

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