Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia

BackgroundAcute 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 remains largely unknown. ResultsUsing an inducible system, we comprehensively analyzed the 3D genome organization in myeloid cells and its reorganization after PML/RAR induction, and performed additional analyses in patient-derived APL cells with native PML/RAR. We discovered 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. ConclusionsOur 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.