Chromatin topology reorganization and transcription repression by PML-RAR? in acute promyeloid leukemia.

ABSTRACT: BACKGROUND:Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML-RAR?, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML-RAR? in leukemogenesis remain largely unknown. RESULTS:Using an inducible system, we comprehensively analyze the 3D genome organization in myeloid cells and its reorganization after PML-RAR? induction and perform additional analyses in patient-derived APL cells with native PML-RAR?. We discover that PML-RAR? mediates extensive chromatin interactions genome-wide. Globally, it redefines the chromatin topology of the myeloid genome toward a more condensed configuration in APL cells; locally, it intrudes RNAPII-associated interaction domains, interrupts myeloid-specific transcription factors binding at enhancers and super-enhancers, and leads to transcriptional repression of genes critical for myeloid differentiation and maturation. CONCLUSIONS:Our results not only provide novel topological insights for the roles of PML-RAR? in transforming myeloid cells into leukemia cells, but further uncover a topological framework of a molecular mechanism for oncogenic fusion proteins in cancers.

SUBMITTER: Wang P 

PROVIDER: S-EPMC7212609 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature