The anaplastic lymphoma kinase controls cell shape and growth of anaplastic large cell lymphoma through Cdc42 activation.
The anaplastic lymphoma kinase controls cell shape and growth of anaplastic large cell lymphoma through Cdc42 activation.
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DOI：
10.1158/0008-5472.can-08-2568
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发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
Chiarle R
中科院分区：
文献类型：
--
作者：
Ambrogio C;Voena C;Manazza AD;Martinengo C;Costa C;Kirchhausen T;Hirsch E;Inghirami G;Chiarle R
间变性大细胞淋巴瘤(ALCL)是一种起源于T细胞的非霍奇金淋巴瘤(NHL)，其表达的致癌融合蛋白来源于间变性大细胞淋巴瘤激酶(ALK)基因的染色体易位或倒位。ALK活性决定了ALCL细胞的增殖和存活。在这里，我们发现核磷蛋白(NPM)-ALK融合的激酶活性以类似于T细胞受体(TCR)刺激的细胞的模式调节ALCL细胞的形状和F-肌动蛋白细丝的组装。NPM-ALK与鸟嘌呤交换因子Vav1形成复合体，通过磷酸化增强其活性。Vav1增加了CDc42的活性，进而调节了ALCL细胞的形态和迁移。在体外，sh-RNA下调Vav1或CDc42的表达，塞克拉明抑制CDc42的活性，导致ALCL细胞周期停滞和细胞凋亡。重要的是，CDC42和NPM-ALK激酶的同时抑制协同作用诱导了ALCL细胞的凋亡。最后，对于体内已经建立的淋巴瘤的生长和维持来说，Cdc42是必需的。因此，我们的数据揭示了通过CDC42调节ALCL细胞生长的机制，从而为新的治疗策略开辟了前景。
Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin Lymphoma (NHL) that originates from T cells and frequently expresses oncogenic fusion proteins derived from chromosomal translocations or inversions of the Anaplastic Lymphoma Kinase (ALK) gene. Proliferation and survival of ALCL cells are determined by the ALK activity. Here we show that the kinase activity of the Nucleophosmin (NPM)-ALK fusion regulated the shape of ALCL cells and F-actin filaments assembly in a pattern similar to T-Cell Receptor (TCR) stimulated cells. NPM-ALK formed a complex with the Guanine Exchange Factor (GEF) VAV1, enhancing its activation through phosphorylation. VAV1 increased Cdc42 activity and, in turn, Cdc42 regulated the shape and the migration of ALCL cells. In vitro knock-down of VAV1 or Cdc42 by sh-RNA, as well as pharmacological inhibition of Cdc42 activity by secramine, resulted in a cell-cycle arrest and apoptosis of ALCL cells. Importantly, the concomitant inhibition of Cdc42 and NPM-ALK kinase acted synergistically to induce apoptosis of ALCL cells. Finally, Cdc42 was necessary for the growth as well as for the maintenance of already established lymphomas in vivo. Thus, our data open perspectives for new therapeutic strategies by revealing a mechanism of regulation of ALCL cells growth through Cdc42.