NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology

ABSTRACT: C-terminal mutation of Nucleophosmin 1 (NPM1C+) was thought to be a primary driving event that reprograms leukemic-associated transcription program to transform hematopoietic stem and progenitor cells (HS/PCs). However, molecular mechanism underlying NPM1C+-driven leukemogenesis remain elusive. Here, we reported that NPM1C+ reprograms MIZ-1/MYC regulatory axis by altering NPM1-associated CTCF-driven topologically associated domains (TADs) that switched the balance of MIZ1 interaction with co-repressors MYC/G9A and coactivator p300 to control cell cycle progress and myeloid lineage-specific PU.1/CEBPa transcription networks. These alterations impaired hematopoietic cell cycle progression and myeloid differentiation. Knock-in of NPM1C+ in bone marrow HSPCs alters cell cycle regulators and myeloid master transcription factor (TF) TAD topology, chromatin accessibility, and gene regulation leading blockage of myeloid differentiation. Retention of NPM1 or reactivation of PU.1 or CEBPa within nucleus activates differentiation program by reorganizing TADs critical for myeloid TFs and cell cycle regulator, leading to blockage of NPM1C+-driven leukemogenesis. Thus, our data revealed that NPM1C+ reshapes CTCF-defined TAD topology to reprogram signature leukemic transcription program require for cell cycle progression and leukemic progression. Restoration of myeloid transcription program in nucleus reversed NPM1C+-driven transcription signature and promotes myeloid differentiation leading to mitigation of AML.

ORGANISM(S): Homo sapiens Mus

PROVIDER: GSE208022 | GEO | 2023/08/09

REPOSITORIES: GEO