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

DOI
https://doi.org/10.3324/haematol.2016.151035
Journal volume & issue
Vol. 102, no. 1

Abstract

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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.