Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas
Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas
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DOI：
10.1182/blood-2005-05-2125
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发表时间：
2006-01-15
期刊：
影响因子：
20.3
通讯作者：
Inghirami, G
中科院分区：
文献类型：
--
作者：
Piva, R;Chiarle, R;Inghirami, G
间变性大细胞淋巴瘤（ALCL）携带染色体易位，其中间变性淋巴瘤激酶（ALK）基因与几个伴侣融合，最常见的是NPM1基因。我们已经证明ALK融合蛋白的组成性激活导致细胞转化和淋巴瘤形成。在此，我们通过使用靶向编码ALK催化结构域的序列的小发夹RNA（shRNA）特异性下调ALK蛋白表达。在体外和体内，ALK消融导致已知ALK下游效应物下调、细胞生长停滞和ALK（+）小鼠胚胎成纤维细胞转化表型逆转。在人ALCL细胞中，慢病毒介导的ALK敲除导致体外G、细胞周期停滞和细胞凋亡以及体内肿瘤生长抑制和消退。使用特定的方法，我们已经证明ALK（+）ALCL的存活和生长严格依赖于ALK激活和信号传导。因此，ALK是治疗干预的可行靶点，其失活可能是治疗ALK淋巴瘤和其他ALK依赖性人类肿瘤的关键方法。
Anaplastic large-cell lymphomas (ALCLs) carry chromosome translocations in which the anaplastic lymphoma kinase (ALK) gene is fused to several partners, most frequently, the NPM1 gene. We have demonstrated that the constitutive activation of ALK fusion proteins results in cellular transformation and lymphoid neoplasia. Herein, we specifically downregulated ALK protein expression by using small hairpin RNA (shRNA) targeting a sequence coding for the catalytic domain of ALK. The ablation of ALK leads to the down-modulation of known ALK downstream effectors, cell growth arrest, and reversion of the transformed phenotype of ALK(+) mouse embryonic fibroblasts in vitro and in vivo. In human ALCL cells lentiviral-mediated ALK knock-down leads to G, cell-cycle arrest and apoptosis in vitro and tumor growth inhibition and regression in vivo. Using a specific approach we have demonstrated that the survival and growth of ALK(+) ALCLs are strictly dependent on ALK activation and signaling. Therefore, ALK is a viable target for therapeutic intervention and its inactivation might represent a pivotal approach for the treatment of ALK lymphomas and other ALK-dependent human tumors.