title: Genome-wide studies identify a novel interplay between AML1 and AML1/ETO in t(8;21) acute myeloid leukemia.
abstract: The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. However, the genome-wide interplay between AML1/ETO and wild-type AML1 remains elusive in the leukemogenesis of t(8;21) AML. Through chromatin immunoprecipitation sequencing and computational analysis, followed by a series of experimental validations, we report here that wild-type AML1 is able to orchestrate the expression of AML1/ETO targets regardless of being activated or repressed; this is achieved via forming a complex with AML1/ETO and via recruiting the cofactor AP-1 on chromatin. On chromatin occupancy, AML1/ETO and wild-type AML1 largely overlap and preferentially bind to adjacent and distinct short and long AML1 motifs on the colocalized regions, respectively. On physical interaction, AML1/ETO can form a complex with wild-type AML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. These findings enrich our knowledge of understanding the significance of the interplay between the wild-type protein and the oncogenic fusion protein in the development of leukemia.
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
authors.forename: Huanwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
authors.forename: Wen
authors.initials: W
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
authors.forename: Yun
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; and.
authors.forename: Hai
authors.initials: H
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; and.
authors.forename: Saijuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; and Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; and Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Kankan
authors.initials: K
authors.lastname: Wang
mesh_terms: D002843:Chromatin / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D005799:Genes, Dominant; D055106:Genome-Wide Association Study; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D000075142:RUNX1 Translocation Partner 1 Protein; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: C107844:AML1-ETO fusion protein, human; D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; D018808:Transcription Factor AP-1