title: ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype.
abstract: Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384 Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.|Department of Pediatrics, St. Luke's International Hospital, Chuo-ku, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hirabayashi
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan kiyokawa-n@ncchd.go.jp oki-kn@ncchd.go.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohki
authors.affiliation: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakabayashi
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Laboratory for Genotyping Development, Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama-shi, Kanagawa, Japan.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Momozawa
authors.affiliation: Department of Systems BioMedicine, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Okamura
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.|Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 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, Setagaya-ku, Tokyo, 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, Setagaya-ku, Tokyo, Japan.|Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Fuchu-shi, Tokyo, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.|Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito-shi, Ibaraki, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ogata-Kawata
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.|Division of Stem Cell Transplant and Cellular Therapy, Children's Cancer Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimura
authors.affiliation: Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba-shi, Chiba, Japan.
authors.forename: Moeko
authors.initials: M
authors.lastname: Hino
authors.affiliation: Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan.
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Kinoshita
authors.affiliation: Department of Haematology/Oncology, Chiba Children's Hospital, Chiba-shi, Chiba, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Kakuda
authors.affiliation: Department of Pediatrics, Dokkyo Medical University, Mibu, Tochigi, Japan.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Kurosawa
authors.affiliation: Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito-shi, Ibaraki, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, Yokohama City University Hospital, Yokohama-shi, Kanagawa, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kajiwara
authors.affiliation: Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Moriwaki
authors.affiliation: Department of Pediatrics, Tokai University School of Medicine, Isehara-shi, Kanagawa, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Morimoto
authors.affiliation: Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Kozue
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Pediatrics, Japanese Red Cross Narita Hospital, Narita-shi, Chiba, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Noguchi
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.|Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Osumi
authors.affiliation: Department of Hematology/Oncology, Nagano Children's Hospital, Azumino-shi, Nagano, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakashita
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.affiliation: Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Fuchu-shi, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yuza
authors.affiliation: Laboratory of Clinical Sequence, Department of Computational biology and medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Koich
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hata
authors.affiliation: Laboratory for Genotyping Development, Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama-shi, Kanagawa, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama-shi, Saitama, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, Chuo-ku, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Manabe
authors.affiliation: Department of Pediatrics, Toho University Omori Medical Center, Ohta-ku, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohara
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan kiyokawa-n@ncchd.go.jp oki-kn@ncchd.go.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kiyokawa
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D059467:Transcriptome; D014178:Translocation, Genetic
chemical_list: D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; C498621:ZNF384 protein, human