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A PML/RARα direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia.
Tan, Yun; Wang, Xiaoling; Song, Huan; Zhang, Yi; Zhang, Rongsheng; Li, Shufen; Jin, Wen; Chen, Saijuan; Fang, Hai; Chen, Zhu; Wang, Kankan.
Afiliación
  • Tan Y; 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.
  • Wang X; 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.
  • Song H; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China; and.
  • Zhang Y; 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.
  • Zhang R; 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.
  • Li S; 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.
  • Jin W; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China; and.
  • Chen S; 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.
  • Fang H; 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.
  • Chen Z; 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.
  • Wang K; 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.
Blood ; 137(11): 1503-1516, 2021 03 18.
Article en En | MEDLINE | ID: mdl-32854112
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Promielocítica Aguda / Regulación Leucémica de la Expresión Génica / Proteínas de Fusión Oncogénica / Proteína de la Leucemia Promielocítica / Receptor alfa de Ácido Retinoico Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Blood Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Promielocítica Aguda / Regulación Leucémica de la Expresión Génica / Proteínas de Fusión Oncogénica / Proteína de la Leucemia Promielocítica / Receptor alfa de Ácido Retinoico Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Blood Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos