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

Hirabayashi, Shinsuke  ,  Ohki, Kentaro  ,  Nakabayashi, Kazuhiko  ,  Ichikawa, Hitoshi  ,  Momozawa, Yukihide  ,  Okamura, Kohji  ,  Yaguchi, Akinori  ,  Terada, Kazuki  ,  Saito, Yuya  ,  Yoshimi, Ai  ,  Ogata-Kawata, Hiroko  ,  Sakamoto, Hiromi  ,  Kato, Motohiro  ,  Fujimura, Junya  ,  Hino, Moeko  ,  Kinoshita, Akitoshi  ,  Kakuda, Harumi  ,  Kurosawa, Hidemitsu  ,  Kato, Keisuke  ,  Kajiwara, Ryosuke  ,  Moriwaki, Koichi  ,  Morimoto, Tsuyoshi  ,  Nakamura, Kozue  ,  Noguchi, Yasushi  ,  Osumi, Tomoo  ,  Sakashita, Kazuo  ,  Takita, Junko  ,  Yuza, Yuki  ,  Matsuda, Koich  ,  Yoshida, Teruhiko  ,  Matsumoto, Kenji  ,  Hata, Kenichiro  ,  Kubo, Michiaki  ,  Matsubara, Yoichi  ,  Fukushima, Takashi  ,  Koh, Katsuyoshi  ,  Manabe, Atsushi  ,  Ohara, Akira  ,  Kiyokawa, Nobutaka

102 ( 1 )  , pp.118 - 129 , 2017-01 , Ferrata storti foundation
ISSN:0390-6078
NCID:AA00660912
Description
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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