
This study investigated the molecular mechanisms underlying the role of the C-terminal mutation of Nucleophosmin 1 (NPM1C+) in driving acute myeloid leukemia (AML). The findings suggest that NPM1C+ activates specific HOX genes and alters the regulation of cell cycle regulators by modifying topologically associated domains (TADs) controlled by CTCF. The introduction of NPM1C+ in hematopoietic cells disrupts TAD topology, resulting in abnormal chromatin accessibility, gene expression, and inhibition of myeloid differentiation. However, restoring NPM1 within the nucleus re-establishes normal differentiation programs by rearranging TADs critical for myeloid transcription factors and cell cycle regulators, thereby preventing NPM1C+-driven leukemogenesis.
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