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 alpha, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML-RAR alpha in leukemogenesis remain largely unknown.ResultsUsing an inducible system, we comprehensively analyze the 3D genome organization in myeloid cells and its reorganization after PML-RAR alpha induction and perform additional analyses in patient-derived APL cells with native PML-RAR alpha. We discover that PML-RAR alpha 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 alpha in transforming myeloid cells into leukemia cells, but further uncover a topological framework of a molecular mechanism for oncogenic fusion proteins in cancers.