High‐risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of high‐risk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients with activating ALK mutations. 8–10% of primary NB patients are ALK‐positive, a figure that increases in the relapsed population. ALK is activated by the ALKAL2 ligand located on chromosome 2p, along with ALK and MYCN, in the “2p‐gain” region associated with NB. Dysregulation of ALK ligand in NB has not been addressed, although one of the first oncogenes described was v‐sis that shares > 90% homology with PDGF. Therefore, we tested whether ALKAL2 ligand could potentiate NB progression in the absence of ALK mutation. We show that ALKAL2 overexpression in mice drives ALK TKI‐sensitive NB in the absence of ALK mutation, suggesting that additional NB patients, such as those exhibiting 2p‐gain, may benefit from ALK TKI‐based therapeutic intervention.

中文翻译：

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ALK 配体 ALKAL2 在没有 ALK 突变的情况下增强 MYCN 驱动的神经母细胞瘤


高风险神经母细胞瘤 (NB) 是造成儿童因癌症死亡人数不成比例的原因。高风险 NB 的指标之一是神经MYC ( MYCN ) 癌基因的扩增，目前这在治疗上是棘手的。间变性淋巴瘤激酶 (ALK) 被鉴定为 NB 癌基因，提高了使用 ALK 酪氨酸激酶抑制剂 (TKI) 治疗具有激活 ALK 突变的患者的可能性。 8-10% 的原发性 NB 患者呈 ALK 阳性，这一数字在复发人群中有所增加。 ALK 被位于染色体 2p 上的 ALKAL2 配体以及ALK和MYCN激活，位于与 NB 相关的“2p-增益”区域。 NB 中 ALK 配体的失调尚未得到解决，尽管最早描述的癌基因之一是v-sis ，它与 PDGF 具有 > 90% 同源性。因此，我们测试了 ALKAL2 配体在没有 ALK 突变的情况下是否可以增强 NB 进展。我们发现，在没有 ALK 突变的情况下，小鼠体内 ALKAL2 过表达会驱动 ALK TKI 敏感的 NB，这表明其他 NB 患者，例如表现出 2p 增益的患者，可能会受益于基于 ALK TKI 的治疗干预。