AI Article Synopsis
- Normal cytogenetic acute myeloid leukemia (AML) often has a TCTG insertion in the NPM1 gene that causes mislocalization of the protein NPM1c to the cytoplasm, yet the mechanisms behind its role in AML are not fully understood.
- This study suggests that the mislocalization of NPM1c disrupts the function of CTCF, a protein critical for DNA looping and gene expression regulation, leading to altered gene expression.
- The researchers confirmed that NPM1c interacts with CTCF, causing CTCF to move to the cytoplasm; by blocking this interaction, CTCF can return to the nucleus and regain its function.
Article Abstract
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.
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| http://dx.doi.org/10.1038/s41375-019-0681-8 | DOI Listing |
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