Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Canada.
Leukemia. 2020 May;34(5):1278-1290. doi: 10.1038/s41375-019-0681-8. Epub 2019 Dec 12.
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.
常染色体核型急性髓细胞白血病（AML）中，核磷蛋白 1（NPM1）第 12 外显子常有 TCTG 插入，导致移码并产生核输出信号（NES），使 NPM1c 定位于细胞质。然而，NPM1c 如何导致 AML 尚未完全阐明。NPM1 参与多种蛋白-蛋白相互作用，其中之一涉及结合因子（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 错误定位到细胞质中，降低了核 CTCF 的功能水平，从而改变了基因表达。我们验证了 CTCF 与 NPM1 的相互作用，并表明 CTCF 与 NPM1c 相互作用，使 CTCF 重新分布到细胞质中。CTCF 与 NPM1c 的相互作用涉及 CTCF 的氨基末端和 NPM1 的最后 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。
