Hiwatari Mitsuteru, Seki Masafumi, Matsuno Ryosuke, Yoshida Kenichi, Nagasawa Takeshi, Sato-Otsubo Aiko, Yamamoto Shohei, Kato Motohiro, Watanabe Kentaro, Sekiguchi Masahiro, Miyano Satoru, Ogawa Seishi, Takita Junko
Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Oncogene. 2022 May;41(20):2789-2797. doi: 10.1038/s41388-022-02301-1. Epub 2022 Apr 11.
The identification of molecular events underlying the pathogenesis of neuroblastoma can likely result in improved clinical outcomes for this disease. In this study, a translocation within chromosome 2p and 4q was found to bring about the formation of an in-frame fusion gene that was composed of portions of the teneurin transmembrane protein 3 (TENM3, also known as ODZ3) gene and the anaplastic lymphoma kinase (ALK) gene in tumor cells from patients with neuroblastoma. Expression of the full length TENM3-ALK cDNA in NIH-3T3 cells led to the formation of a fusion protein that: (1) possesses constitutive tyrosine kinase activity, (2) induces strong activation of the downstream targets of extracellular signal-regulated kinase (ERK), protein kinase B (a.k.a. AKT), and signal transducer and activator of transcription 3 (STAT3), (3) provokes oncogenic transformation in NOD.Cg-PrkdcIl2rg/ShiJic mice, and (4) possesses sensitivity to ALK inhibitors in vitro and in vivo. Our findings demonstrated that patients with neuroblastoma may express a transforming fusion kinase, which is a promising candidate for a therapeutic target and a diagnostic molecular marker for neuroblastoma. The in-frame 5' partner gene that fuses with ALK has not been reported previously in neuroblastoma. Our data provide novel biological insights into the mechanism of ALK activation due to translocation, with implications for neuroblastoma tumorigenesis, and could be useful as a vital marker for the accurate diagnosis of this type of neuroblastoma.
确定神经母细胞瘤发病机制背后的分子事件可能会改善该疾病的临床治疗效果。在本研究中，发现2号染色体和4号染色体之间的易位导致了一个读码框内融合基因的形成，该融合基因由神经母细胞瘤患者肿瘤细胞中的teneurin跨膜蛋白3（TENM3，也称为ODZ3）基因和间变性淋巴瘤激酶（ALK）基因的部分组成。全长TENM3-ALK cDNA在NIH-3T3细胞中的表达导致形成一种融合蛋白，该融合蛋白：（1）具有组成型酪氨酸激酶活性，（2）诱导细胞外信号调节激酶（ERK）、蛋白激酶B（也称为AKT）和信号转导与转录激活因子3（STAT3）的下游靶点强烈激活，（3）在NOD.Cg-PrkdcIl2rg/ShiJic小鼠中引发致癌转化，（4）在体外和体内对ALK抑制剂敏感。我们的研究结果表明，神经母细胞瘤患者可能表达一种转化融合激酶，这是一个有前景的治疗靶点候选物和神经母细胞瘤的诊断分子标志物。与ALK融合的读码框内5'伙伴基因在神经母细胞瘤中此前尚未见报道。我们的数据为由于易位导致的ALK激活机制提供了新的生物学见解，对神经母细胞瘤的肿瘤发生具有重要意义，并且可作为准确诊断此类神经母细胞瘤的重要标志物。
