학술논문
ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype
Document Type
article
Author
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
Source
Haematologica, Vol 102, Iss 1 (2017)
Subject
Language
English
ISSN
0390-6078
1592-8721
1592-8721
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.