JGM, JMG, JAXCC
Genome Biol 2020 May 11; 21(1):110
HG009409,DK107967,RGP0039,Roux Family Endowment,CA034196
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.
Wang, Ping; Tang, Zhonghui; Lee, Byoungkoo; Zhu, Jacqueline Jufen; Cai, Liuyang; Szalaj, Przemyslaw; Tian, Simon Zhongyuan; Zheng, Meizhen; Plewczynski, Dariusz; Ruan, Xiaoan; Liu, Edison T; Wei, Chia-Lin; and Ruan, Yijun, "Chromatin topology reorganization and transcription repression by PML-RARα in acute promyeloid leukemia." (2020). Faculty Research 2020. 84.