Haematologica (Jan 2017)
ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype
- Shinsuke Hirabayashi,
- Kentaro Ohki,
- Kazuhiko Nakabayashi,
- Hitoshi Ichikawa,
- Yukihide Momozawa,
- Kohji Okamura,
- Akinori Yaguchi,
- Kazuki Terada,
- Yuya Saito,
- Ai Yoshimi,
- Hiroko Ogata-Kawata,
- Hiromi Sakamoto,
- Motohiro Kato,
- Junya Fujimura,
- Moeko Hino,
- Akitoshi Kinoshita,
- Harumi Kakuda,
- Hidemitsu Kurosawa,
- Keisuke Kato,
- Ryosuke Kajiwara,
- Koichi Moriwaki,
- Tsuyoshi Morimoto,
- Kozue Nakamura,
- Yasushi Noguchi,
- Tomoo Osumi,
- Kazuo Sakashita,
- Junko Takita,
- Yuki Yuza,
- Koich Matsuda,
- Teruhiko Yoshida,
- Kenji Matsumoto,
- Kenichiro Hata,
- Michiaki Kubo,
- Yoichi Matsubara,
- Takashi Fukushima,
- Katsuyoshi Koh,
- Atsushi Manabe,
- Akira Ohara,
- Nobutaka Kiyokawa
Affiliations
- Shinsuke Hirabayashi
- 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
- Kentaro Ohki
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
- Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
- Hitoshi Ichikawa
- Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Yukihide Momozawa
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama-shi, Kanagawa, Japan
- Kohji Okamura
- Department of Systems BioMedicine, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
- Akinori Yaguchi
- 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
- Kazuki Terada
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
- Yuya Saito
- 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
- Ai Yoshimi
- 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
- Hiroko Ogata-Kawata
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
- Hiromi Sakamoto
- Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Motohiro Kato
- 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
- Junya Fujimura
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
- Moeko Hino
- Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba-shi, Chiba, Japan
- Akitoshi Kinoshita
- Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan
- Harumi Kakuda
- Department of Haematology/Oncology, Chiba Children’s Hospital, Chiba-shi, Chiba, Japan
- Hidemitsu Kurosawa
- Department of Pediatrics, Dokkyo Medical University, Mibu, Tochigi, Japan
- Keisuke Kato
- Division of Pediatric Hematology and Oncology, Ibaraki Children’s Hospital, Mito-shi, Ibaraki, Japan
- Ryosuke Kajiwara
- Department of Pediatrics, Yokohama City University Hospital, Yokohama-shi, Kanagawa, Japan
- Koichi Moriwaki
- Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan
- Tsuyoshi Morimoto
- Department of Pediatrics, Tokai University School of Medicine, Isehara-shi, Kanagawa, Japan
- Kozue Nakamura
- Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
- Yasushi Noguchi
- Department of Pediatrics, Japanese Red Cross Narita Hospital, Narita-shi, Chiba, Japan
- Tomoo Osumi
- 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
- Kazuo Sakashita
- Department of Hematology/Oncology, Nagano Children’s Hospital, Azumino-shi, Nagano, Japan
- Junko Takita
- Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
- Yuki Yuza
- Department of Hematology/Oncology, Tokyo Metropolitan Children’s Medical Center, Fuchu-shi, Tokyo, Japan
- Koich Matsuda
- Laboratory of Clinical Sequence, Department of Computational biology and medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo, Japan
- Teruhiko Yoshida
- Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Kenji Matsumoto
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
- Kenichiro Hata
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
- Michiaki Kubo
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama-shi, Kanagawa, Japan
- Yoichi Matsubara
- National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
- Takashi Fukushima
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan
- Katsuyoshi Koh
- Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama-shi, Saitama, Japan
- Atsushi Manabe
- Department of Pediatrics, St. Luke’s International Hospital, Chuo-ku, Tokyo, Japan
- Akira Ohara
- Department of Pediatrics, Toho University Omori Medical Center, Ohta-ku, Tokyo, Japan
- Nobutaka Kiyokawa
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan
- DOI
- https://doi.org/10.3324/haematol.2016.151035
- Journal volume & issue
-
Vol. 102,
no. 1
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.