Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China; and.
Blood. 2021 Mar 18;137(11):1503-1516. doi: 10.1182/blood.2020005698.
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-α (PML/RARα), 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/RARα 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/RARα 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/RARα-regulated targets in APL cells. We use a series of in vitro and in vivo experiments to demonstrate that PML/RARα-activated target gene GFI1 is necessary for the maintenance of APL cells and that PML/RARα, 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/RARα 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.
致癌融合蛋白引发的转录失调在白血病中起着至关重要的作用。目前的观点认为，由染色体易位 t(15;17)产生的早幼粒细胞白血病/维甲酸受体-α (PML/RARα) 致癌融合蛋白在急性早幼粒细胞白血病 (APL) 中作为转录抑制剂发挥作用。在这里，我们提供了丰富的证据表明 PML/RARα 如何通过抑制和激活功能驱动肿瘤发生，特别是新发现的 PML/RARα 在 APL 白血病发生中的激活作用的重要性。PML/RARα 的激活功能是通过招募大量的 P300 和 HDAC1 以及形成超级增强子来实现的。全反式维甲酸和三氧化二砷是 APL 治疗中两种广泛使用的药物，它们在控制 APL 细胞中超增强子相关 PML/RARα 调节靶标方面具有协同作用。我们使用一系列体外和体内实验证明，PML/RARα 激活的靶基因 GFI1 对于维持 APL 细胞是必需的，并且 PML/RARα 可能通过超级增强子区域的染色质构象来转录激活 GFI1。最后，我们对 GFI1 靶基因进行了分析，并揭示了 GFI1 和 PML/RARα 在共同调节靶基因方面在染色质上的相互作用。我们的研究为融合转录因子在转录失调中驱动白血病发生的双重作用提供了基因组见解，强调了全面剖析调节回路的重要性。
