A PML/RARα direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia

Transcriptional deregulation initiated by oncogenic fusion proteins plays a vital role in leukemia. The prevailing view is that the oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor-alpha (PML/RAR alpha), generated by the chromosome translocation t(15; 17), functions as a transcriptional repressor in acute promyelocytic leukemia (APL). Here, we provide rich evidence of how PML/RAR alpha drives oncogenesis through both repressive and activating functions, particularly the importance of the newly identified activation role for the leukemogenesis of APL. The activating function of PML/RAR alpha is achieved by recruiting both abundant P300 and HDAC1 and by the formation of super-enhancers. All-trans retinoic acid and arsenic trioxide, 2 widely used drugs in APL therapy, exert synergistic effects on controlling super-enhancer-associated PML/RAR alpha-regulated targets in APL cells. We use a series of in vitro and in vivo experiments to demonstrate that PML/RAR alpha-activated target gene GFI1 is necessary for the maintenance of APL cells and that PML/RAR alpha, likely oligomerized, transactivates GFI1 through chromatin conformation at the super-enhancer region. Finally, we profile GFI1 targets and reveal the interplay between GFI1 and PML/RAR alpha on chromatin in coregulating target genes. Our study provides genomic insight into the dual role of fusion transcription factors in transcriptional deregulation to drive leukemia development, highlighting the importance of globally dissecting regulatory circuits.

Automated summary

The activation function of PML/RAR alpha through recruiting P300 and HDAC1 and forming super-enhancers, and its synergistic effects with all-trans retinoic acid and arsenic trioxide in controlling super-enhancer-associated PML/RAR alpha-regulated targets in APL cells are highlighted. The study demonstrated the necessity of the PML/RAR alpha-activated target gene GFI1 for maintaining APL cells and the interplay between GFI1 and PML/RAR alpha in coregulating target genes on chromatin. Genomic insight into the dual role of fusion transcription factors in transcriptional deregulation to drive leukemia development is provided, emphasizing the importance of globally dissecting regulatory circuits.