Chromatin topology reorganization and transcription repression by PML-RARα in acute promyeloid leukemia
Ping Wang, Zhonghui Tang, Byoungkoo Lee, Jacqueline Jufen Zhu, Liuyang Cai, Przemysław Szałaj, Simon Zhongyuan Tian, Meizhen Zheng, Dariusz Plewczyński, Xiaoan Ruan, Edison T. Liu, Chia‐Lin Wei, Yijun Ruan
Abstract
BACKGROUND: Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML-RARα, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML-RARα 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-RARα induction and perform additional analyses in patient-derived APL cells with native PML-RARα. We discover that PML-RARα 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-RARα in transforming myeloid cells into leukemia cells, but further uncover a topological framework of a molecular mechanism for oncogenic fusion proteins in cancers.