29Jun 2023
NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology

NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology

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.

  • #oncology

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