Oncogenic mutations of ALK kinase in neuroblastoma

被引:690
作者
Chen, Yuyan [2 ,3 ]
Takita, Junko [1 ,2 ,3 ]
Choi, Young Lim [1 ,4 ]
Kato, Motohiro [2 ,3 ]
Ohira, Miki [5 ]
Sanada, Masashi [1 ,3 ,6 ]
Wang, Lili [1 ,3 ,6 ]
Soda, Manabu [4 ]
Kikuchi, Akira [7 ]
Igarashi, Takashi [2 ]
Nakagawara, Akira [5 ]
Hayashi, Yasuhide [8 ]
Mano, Hiroyuki [4 ,6 ]
Ogawa, Seishi [1 ,3 ,6 ]
机构
[1] Univ Tokyo, Cell Therapy & Transplantat Med, Tokyo 1138655, Japan
[2] Univ Tokyo, Dept Pediat, Tokyo 1138655, Japan
[3] Univ Tokyo, Canc Genom Project, Grad Sch Med, Tokyo 1138655, Japan
[4] Jichi Med Univ, Div Funct Genom, Toguchi 3290498, Japan
[5] Chiba Canc Ctr, Res Inst, Div Biochem, Chiba 2608717, Japan
[6] Japan Sci & Technol Agcy, Kawaguchi, Saitama 3320012, Japan
[7] Saitama Childrens Med Ctr, Div Hematol Oncol, Saitama 3398551, Japan
[8] Gunma Childrens Med Ctr, Shibukawa 3778577, Japan
基金
日本科学技术振兴机构;
关键词
D O I
10.1038/nature07399
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Neuroblastoma in advanced stages is one of the most intractable paediatric cancers, even with recent therapeutic advances(1). Neuroblastoma harbours a variety of genetic changes, including a high frequency of MYCN amplification, loss of heterozygosity at 1p36 and 11q, and gain of genetic material from 17q, all of which have been implicated in the pathogenesis of neuroblastoma(2-5). However, the scarcity of reliable molecular targets has hampered the development of effective therapeutic agents targeting neuroblastoma. Here we show that the anaplastic lymphoma kinase (ALK), originally identified as a fusion kinase in a subtype of non- Hodgkin's lymphoma (NPM-ALK)(6-8) and more recently in adenocarcinoma of lung (EML4-ALK)(9,10), is also a frequent target of genetic alteration in advanced neuroblastoma. According to our genome- wide scans of genetic lesions in 215 primary neuroblastoma samples using high- density single- nucleotide polymorphism genotyping microarrays(11-14), the ALK locus, centromeric to the MYCN locus, was identified as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed eight novel missense mutations in 13 out of 215 (6.1%) fresh tumours and 8 out of 24 ( 33%) neuroblastoma- derived cell lines. All but one mutation in the primary samples ( 12 out of 13) were found in stages 3 - 4 of the disease and were harboured in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wild- type kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumours in nude mice. Furthermore, we demonstrate that downregulation of ALK through RNA interference suppresses proliferation of neuroblastoma cells harbouring mutated ALK. We anticipate that our findings will provide new insights into the pathogenesis of advanced neuroblastoma and that ALK- specific kinase inhibitors might improve its clinical outcome.
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收藏
页码:971 / U56
页数:5
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