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Haematologica. 2017 Jan;102(1):118-129. doi: 10.3324/haematol.2016.151035. Epub 2016 Sep 15.

ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype.

Author information

1
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
2
Department of Pediatrics, St. Luke's International Hospital, Chuo-ku, Tokyo, Japan.
3
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.
4
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
5
Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
6
Laboratory for Genotyping Development, Center for Integrative Medical Sciences (IMS), RIKEN, Yokohama-shi, Kanagawa, Japan.
7
Department of Systems BioMedicine, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
8
Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
9
Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Fuchu-shi, Tokyo, Japan.
10
Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito-shi, Ibaraki, Japan.
11
Division of Stem Cell Transplant and Cellular Therapy, Children's Cancer Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
12
Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba-shi, Chiba, Japan.
13
Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan.
14
Department of Haematology/Oncology, Chiba Children's Hospital, Chiba-shi, Chiba, Japan.
15
Department of Pediatrics, Dokkyo Medical University, Mibu, Tochigi, Japan.
16
Department of Pediatrics, Yokohama City University Hospital, Yokohama-shi, Kanagawa, Japan.
17
Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan.
18
Department of Pediatrics, Tokai University School of Medicine, Isehara-shi, Kanagawa, Japan.
19
Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.
20
Department of Pediatrics, Japanese Red Cross Narita Hospital, Narita-shi, Chiba, Japan.
21
Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
22
Department of Hematology/Oncology, Nagano Children's Hospital, Azumino-shi, Nagano, Japan.
23
Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
24
Laboratory of Clinical Sequence, Department of Computational biology and medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo, Japan.
25
Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
26
National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
27
Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan.
28
Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama-shi, Saitama, Japan.
29
Department of Pediatrics, Toho University Omori Medical Center, Ohta-ku, Tokyo, Japan.

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.

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