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
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.
Haematologica. 2017 Jan;102(1):118-129. doi: 10.3324/haematol.2016.151035. Epub 2016 Sep 15.
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.
最近在B细胞前体急性淋巴细胞白血病中发现了涉及ZNF384的融合基因，并且已经报道了7种融合伴侣。我们通过全转录组测序和/或聚合酶链反应进一步对这种类型的融合基因进行了表征。除了先前报道的基因外，我们还鉴定出BMP2K是ZNF384的一种新型融合伴侣。包括我们最近报道的EP300-ZNF384，在一项单一临床试验入组的291例B细胞前体急性淋巴细胞白血病患者中，ZNF384相关融合基因的总发生率为4.1%，其中TCF3-ZNF384最为常见，发生率为2.4%。具有弱CD10以及异常CD13和/或CD33表达的特征性免疫表型被揭示为携带ZNF384相关融合基因的白血病细胞的共同特征。TCF3-ZNF384阳性患者的特征性基因表达谱富含造血干细胞特征，并且与EP300-ZNF384阳性患者的相关，但与TCF3-PBX1阳性和ZNF384融合阴性患者的明显不同。然而，TCF3-ZNF384阳性患者的临床特征与EP300-ZNF384阳性患者明显不同，表现为就诊时细胞计数更高且年龄更小。TCF3-ZNF384阳性患者显示出明显更差的类固醇反应和更高的复发频率，并且在一些病例中通过全外显子组分析检测到RAS信号通路基因存在额外的激活突变。我们的观察结果表明，ZNF384相关融合基因构成了B细胞前体急性淋巴细胞白血病的一个独特亚组，具有特征性免疫表型，而临床特征取决于各个融合伴侣的功能特性。
