最近發(fā)現(xiàn)在10％的散發(fā)神經(jīng)母細(xì)胞瘤和大多數(shù)家族性神經(jīng)母細(xì)胞瘤患者中,，存在激活的間變性淋巴瘤激酶（ALK）基因突變，,。然而,，在腫瘤發(fā)生中ALK突變的作用仍然是難以捉摸的。
7月4日,，Sci Transl Med雜志報(bào)道,，有針對(duì)性的表達(dá)最常見和最具侵襲性的突變類型ALK-F1174L可誘發(fā)小鼠的神經(jīng)母細(xì)胞瘤。這些誘發(fā)的小鼠腫瘤在形態(tài),，轉(zhuǎn)移模式,，基因表達(dá)等方面均與人類神經(jīng)母細(xì)胞瘤相似。并且,，小鼠腫瘤同樣存在神經(jīng)分泌囊泡以及突觸結(jié)構(gòu),。
這個(gè)ALK驅(qū)動(dòng)的神經(jīng)母細(xì)胞瘤小鼠模型的精確模擬再現(xiàn)了該疾病的基因譜。神經(jīng)母細(xì)胞瘤小鼠模型的染色體畸變類似于那些在人類神經(jīng)母細(xì)胞瘤發(fā)生的畸變,，包括17Q增益和MYCN基因擴(kuò)增,。針對(duì)性的ALK-F1174L和MYCN基因共表達(dá)顯示了強(qiáng)大的協(xié)同作用，能以最小的染色體畸變誘導(dǎo)出神經(jīng)母細(xì)胞瘤,。這提示如果兩種癌基因蛋白同時(shí)發(fā)生突變,，則腫瘤的誘發(fā)僅需要較少的二次基因突變打擊即可發(fā)生。
應(yīng)用ALK抑制劑TAE-684治療ALK-F1174L轉(zhuǎn)基因小鼠,，可誘導(dǎo)的腫瘤完全消退,。這表明腫瘤細(xì)胞依賴于ALK-F1174L活性,。研究者認(rèn)為：在ALK的激酶結(jié)構(gòu)域的激活突變足以誘導(dǎo)神經(jīng)母細(xì)胞瘤的發(fā)生，ALK抑制劑對(duì)于治療ALK突變的人類神經(jīng)母細(xì)胞瘤具有很好的應(yīng)用前景,。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
PMC:
PMID:
Targeted Expression of Mutated ALK Induces Neuroblastoma in Transgenic Mice
Lukas C. Heukamp1,*,Theresa Thor2,*,Alexander Schramm2,Katleen De Preter3,Candy Kumps3,Bram De Wilde3,Andrea Odersky2,Martin Peifer4,5,Sven Lindner2,Annika Spruessel2,Filip Pattyn3,Pieter Mestdagh3,Bj?rn Menten3,Steffi Kuhfittig-Kulle2,Annette Künkele2,Katharina K?nig1,Lydia Meder1,Sampurna Chatterjee4,Roland T. Ullrich4,Stefanie Schulte2,Jo Vandesompele3,Frank Speleman3,Reinhard Büttner1,Angelika Eggert2 andJohannes H. Schulte2,?
Activating anaplastic lymphoma kinase (ALK) mutations were recently detected in most familial and 10% of sporadic neuroblastomas. However, the role of mutated ALK in tumorigenesis remains elusive. We demonstrate that targeted expression of the most frequent and aggressive variant, ALKF1174L, is tumorigenic in mice. Tumors resembled human neuroblastomas in morphology, metastasis pattern, gene expression, and the presence of neurosecretory vesicles as well as synaptic structures. This ALK-driven neuroblastoma mouse model precisely recapitulated the genetic spectrum of the disease. Chromosomal aberrations were syntenic to those in human neuroblastoma, including 17q gain and MYCN oncogene amplification. Targeted ALKF1174L and MYCN coexpression revealed a strong synergism in inducing neuroblastoma with minimal chromosomal aberrations, suggesting that fewer secondary hits are required for tumor induction if both oncoproteins are targeted. Treatment of ALKF1174L transgenic mice with the ALK inhibitor TAE-684 induced complete tumor regression, indicating that tumor cells were addicted to ALKF1174L activity. We conclude that an activating mutation within the ALK kinase domain is sufficient to induce neuroblastoma development, and ALK inhibitors show promise for treating human neuroblastomas harboring ALK mutations.
