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ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype.
Haematologica 2017; 102(1):118-129H

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+Show Affiliations

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.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.Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.Laboratory for Genotyping Development, Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama-shi, Kanagawa, Japan.Department of Systems BioMedicine, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.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.Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.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.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.Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.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.Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba-shi, Chiba, Japan.Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan.Department of Haematology/Oncology, Chiba Children's Hospital, Chiba-shi, Chiba, Japan.Department of Pediatrics, Dokkyo Medical University, Mibu, Tochigi, Japan.Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito-shi, Ibaraki, Japan.Department of Pediatrics, Yokohama City University Hospital, Yokohama-shi, Kanagawa, Japan.Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan.Department of Pediatrics, Tokai University School of Medicine, Isehara-shi, Kanagawa, Japan.Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.Department of Pediatrics, Japanese Red Cross Narita Hospital, Narita-shi, Chiba, Japan.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.Department of Hematology/Oncology, Nagano Children's Hospital, Azumino-shi, Nagano, Japan.Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Fuchu-shi, Tokyo, Japan.Laboratory of Clinical Sequence, Department of Computational biology and medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo, Japan.Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.Laboratory for Genotyping Development, Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama-shi, Kanagawa, Japan.National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan.Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama-shi, Saitama, Japan.Department of Pediatrics, St. Luke's International Hospital, Chuo-ku, Tokyo, Japan.Department of Pediatrics, Toho University Omori Medical Center, Ohta-ku, Tokyo, Japan.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.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27634205

Citation

Hirabayashi, Shinsuke, et al. "ZNF384-related Fusion Genes Define a Subgroup of Childhood B-cell Precursor Acute Lymphoblastic Leukemia With a Characteristic Immunotype." Haematologica, vol. 102, no. 1, 2017, pp. 118-129.
Hirabayashi S, Ohki K, Nakabayashi K, et al. ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica. 2017;102(1):118-129.
Hirabayashi, S., Ohki, K., Nakabayashi, K., Ichikawa, H., Momozawa, Y., Okamura, K., ... Kiyokawa, N. (2017). ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica, 102(1), pp. 118-129. doi:10.3324/haematol.2016.151035.
Hirabayashi S, et al. ZNF384-related Fusion Genes Define a Subgroup of Childhood B-cell Precursor Acute Lymphoblastic Leukemia With a Characteristic Immunotype. Haematologica. 2017;102(1):118-129. PubMed PMID: 27634205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. AU - Hirabayashi,Shinsuke, AU - Ohki,Kentaro, AU - Nakabayashi,Kazuhiko, AU - Ichikawa,Hitoshi, AU - Momozawa,Yukihide, AU - Okamura,Kohji, AU - Yaguchi,Akinori, AU - Terada,Kazuki, AU - Saito,Yuya, AU - Yoshimi,Ai, AU - Ogata-Kawata,Hiroko, AU - Sakamoto,Hiromi, AU - Kato,Motohiro, AU - Fujimura,Junya, AU - Hino,Moeko, AU - Kinoshita,Akitoshi, AU - Kakuda,Harumi, AU - Kurosawa,Hidemitsu, AU - Kato,Keisuke, AU - Kajiwara,Ryosuke, AU - Moriwaki,Koichi, AU - Morimoto,Tsuyoshi, AU - Nakamura,Kozue, AU - Noguchi,Yasushi, AU - Osumi,Tomoo, AU - Sakashita,Kazuo, AU - Takita,Junko, AU - Yuza,Yuki, AU - Matsuda,Koich, AU - Yoshida,Teruhiko, AU - Matsumoto,Kenji, AU - Hata,Kenichiro, AU - Kubo,Michiaki, AU - Matsubara,Yoichi, AU - Fukushima,Takashi, AU - Koh,Katsuyoshi, AU - Manabe,Atsushi, AU - Ohara,Akira, AU - Kiyokawa,Nobutaka, AU - ,, Y1 - 2016/09/15/ PY - 2016/06/14/received PY - 2016/09/14/accepted PY - 2016/9/17/pubmed PY - 2017/7/1/medline PY - 2016/9/17/entrez SP - 118 EP - 129 JF - Haematologica JO - Haematologica VL - 102 IS - 1 N2 - 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. SN - 1592-8721 UR - https://www.unboundmedicine.com/medline/citation/27634205/ZNF384_related_fusion_genes_define_a_subgroup_of_childhood_B_cell_precursor_acute_lymphoblastic_leukemia_with_a_characteristic_immunotype_ L2 - http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=27634205 DB - PRIME DP - Unbound Medicine ER -