title: EP300-ZNF384 fusion gene product up-regulates GATA3 gene expression and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells.
abstract: ZNF384-related fusion genes are associated with a distinct subgroup of B-cell precursor acute lymphoblastic leukemias in childhood, with a frequency of approximately 3-4%. We previously identified a novel EP300-ZNF384 fusion gene. Patients with the ZNF384-related fusion gene exhibit a hematopoietic stem cell (HSC) gene expression signature and characteristic immunophenotype with negative or low expression of CD10 and aberrant expression of myeloid antigens, such as CD33 and CD13. However, the molecular basis of this pathogenesis remains completely unknown. In the present study, we examined the biological effects of EP300-ZNF384 expression induced by retrovirus-mediated gene transduction in an REH B-cell precursor acute lymphoblastic leukemia cell line, and observed the acquisition of the HSC gene expression signature and an up-regulation of GATA3 gene expression, as assessed by microarray analysis. In contrast, the gene expression profile induced by wild-type ZNF384 in REH cells was significantly different from that by EP300-ZNF384 expression. Together with the results of reporter assays, which revealed the enhancement of GATA3-promoter activity by EP300-ZNF384 expression, these findings suggest that EP300-ZNF384 mediates GATA3 gene expression and may be involved in the acquisition of the HSC gene expression signature and characteristic immunophenotype in B-cell precursor acute lymphoblastic leukemia cells.
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.|Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yaguchi
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.|Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Terada
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ueno-Yokohata
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimura
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohki
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Manabe
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. kiyokawa-n@ncchd.go.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kiyokawa
mesh_terms: D045744:Cell Line, Tumor; D002648:Child; D050881:E1A-Associated p300 Protein / Q000235:genetics* / Q000502:physiology; D050990:GATA3 Transcription Factor / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D050939:Gene Fusion / Q000235:genetics* / Q000502:physiology; D006412:Hematopoietic Stem Cells; D006801:Humans; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D015534:Trans-Activators; C498621:ZNF384 protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: CD33; EP300; GATA3; Transcription; ZNF384