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Oncogenic mutations of ALK kinase in neuroblastoma

机译：神经母细胞瘤中ALK激酶的致癌突变

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Neuroblastoma in advanced stages is one of the most intractable paediatric cancers, even with recent therapeutic advances. Neuroblastoma harbours a variety of genetic changes, including a high frequency of MYCN amplification, loss of hetero2ygosity at 1p36 and 11q, and gain of genetic material from 17q, all of which have been implicated in the pathogenesis of neuroblastoma. 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) and more recently in adenocarcinoma of lung (EML4-ALK), 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, 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.
机译：晚期神经母细胞瘤是最难治的小儿癌症之一，即使在最近的治疗进展中也是如此。神经母细胞瘤具有多种遗传变化，包括MYCN扩增的频率高，1p36和11q处杂合性的丧失以及17q基因的遗传物质的增加，所有这些都与神经母细胞瘤的发病机理有关。然而，可靠分子靶标的缺乏阻碍了靶向神经母细胞瘤的有效治疗剂的开发。在这里我们显示，间变性淋巴瘤激酶（ALK）最初是非霍奇金淋巴瘤（NPM-ALK）亚型中的融合激酶，最近在肺腺癌（EML4-ALK）中也被确定为融合激酶晚期神经母细胞瘤的遗传改变。根据我们使用高密度单核苷酸多态性基因分型微阵列对215个原发性神经母细胞瘤样品进行遗传损伤全基因组扫描的结果，与MYCN基因座着重的ALK基因座被确定为拷贝数增加和基因扩增的复发靶标。此外，ALK的DNA测序显示，在215个新肿瘤（占6.1％）中的13个中，有8个新的错义突变，在24个神经母细胞瘤衍生的细胞系中，有24个（33％）中的8个。在该疾病的第3-4阶段发现了一次样本中的所有突变（13个中的12个），并且都存在于激酶结构域中。与野生型激酶相比，突变的激酶被自磷酸化并显示出增加的激酶活性。他们能够转化NIH3T3成纤维细胞，如其在软琼脂中的集落形成能力和在裸鼠中形成肿瘤的能力所表明的。此外，我们证明通过RNA干扰对ALK的下调抑制了携带突变的ALK的成神经细胞瘤细胞的增殖。我们预计我们的发现将为晚期神经母细胞瘤的发病机理提供新的见解，并且ALK特异性激酶抑制剂可能会改善其临床疗效。

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