NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology.

ABSTRACT: C-terminal mutation of Nucleophosmin 1 (NPM1^C+) was thought to be a primary driving event in acute myeloid leukemia (AML) that reprograms leukemic-associated transcription programs to transform hematopoietic stem and progenitor cells (HSPCs). However, molecular mechanisms underlying NPM1^C+-driven leukemogenesis remain elusive. Here, we report that NPM1^C+ activates signature HOX genes and reprograms cell cycle regulators by altering CTCF-driven topologically associated domains (TADs). Hematopoietic-specific NPM1^C+ knock-in alters TAD topology leading to disrupted regulation of the cell cycle as well as aberrant chromatin accessibility and homeotic gene expression, which results in myeloid differentiation block. Restoration of NPM1 within the nucle

SUBMITTER: Lai Q 

PROVIDER: S-EPMC10400418 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature