title: Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ-TIF2 fusion.
abstract: Chromosomal translocations that involve the monocytic leukemia zinc finger (MOZ) gene are typically associated with human acute myeloid leukemia (AML) and often predict a poor prognosis. Overexpression of HOXA9, HOXA10, and MEIS1 was observed in AML patients with MOZ fusions. To assess the functional role of HOX upregulation in leukemogenesis by MOZ-TIF2, we focused on bromodomain-PHD finger protein 1 (BRPF1), a component of the MOZ complex that carries out histone acetylation for generating and maintaining proper epigenetic programs in hematopoietic cells. Immunoprecipitation analysis showed that MOZ-TIF2 forms a stable complex with BRPF1, and chromatin immunoprecipitation analysis showed that MOZ-TIF2 and BRPF1 interact with HOX genes in MOZ-TIF2-induced AML cells. Depletion of BRPF1 decreased the MOZ localization on HOX genes, resulting in loss of transformation ability induced by MOZ-TIF2. Furthermore, mutant MOZ-TIF2 engineered to lack histone acetyltransferase activity was incapable of deregulating HOX genes as well as initiating leukemia. These data indicate that MOZ-TIF2/BRPF1 complex upregulates HOX genes mediated by MOZ-dependent histone acetylation, leading to the development of leukemia. We suggest that activation of BRPF1/HOX pathway through MOZ HAT activity is critical for MOZ-TIF2 to induce AML.
authors.affiliation: Division of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Haruko
authors.initials: H
authors.lastname: Shima
authors.forename: Kazutsune
authors.initials: K
authors.lastname: Yamagata
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Aikawa
authors.forename: Mika
authors.initials: M
authors.lastname: Shino
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Issay
authors.initials: I
authors.lastname: Kitabayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C086011:BRPF1 protein, human; D000092468:Bromodomain Containing Proteins; C475973:MOZ-TIF2 protein, human; C097899:homeobox protein HOXA9; C069634:HOXA10 protein, human; C108712:KAT6A protein, human