Chiarle Roberto, Gong Jerald Z, Guasparri Ilaria, Pesci Anna, Cai Jonjing, Liu Jian, Simmons William J, Dhall Girish, Howes Jennifer, Piva Roberto, Inghirami Giorgio
Department of Pathology and Kaplan Comprehensive Cancer Center, and Department of Pediatric Oncology, New York University School of Medicine, New York, NY 10016, USA.
Blood. 2003 Mar 1;101(5):1919-27. doi: 10.1182/blood-2002-05-1343. Epub 2002 Nov 7.
Anaplastic Large Cell Lymphomas (ALCLs) carry translocations in which the anaplastic lymphoma kinase (ALK) gene is juxtaposed to various genes, the most common of which is the NPM/B23 gene. ALK fusion proteins result in the constitutive activation of ALK tyrosine kinase, thereby enhancing proliferation and increasing cell survival. A direct role for NPM-ALK in cellular transformation has been shown in vitro with immortalized cell lines and in vivo using retroviral transfer experiments. Nonetheless, there is no direct evidence of its oncogenic potential in T lymphocytes, which represent the most common target of ALK chimeras. Here, we describe a new mouse model of lymphomagenesis in which human NPM-ALK transcription was targeted to T cells. NPM-ALK transgenic (Tg) mice were born with the expected mendelian distribution, normal lymphoid organs, and a normal number and proportion of helper and suppressor T cells. However, after a short period of latency, all NPM-ALK Tg mice developed malignant lymphoproliferative disorders (mean survival, 18 weeks). NPM-ALK Tg thymic lymphomas displayed a T-cell phenotype characteristic of immature thymocytes and frequently coexpressed surface CD30. A subset of the NPM-ALK Tg mice also developed clonal B-cell plasma cell neoplasms. These tumors arose in peripheral lymphoid organs (plasmacytomas) or within the bone marrow and often led to peripheral neuropathies and limb paralysis. Our NPM-ALK Tg mice are a suitable model to dissect the molecular mechanisms of ALK-mediated transformation and to investigate the efficacy of new therapeutic approaches for the treatment of human ALCL in vivo.
间变性大细胞淋巴瘤（ALCLs）存在易位情况，即间变性淋巴瘤激酶（ALK）基因与多种基因并列，其中最常见的是核仁磷酸蛋白/B23基因。ALK融合蛋白导致ALK酪氨酸激酶的组成性激活，从而增强增殖并提高细胞存活率。在体外使用永生化细胞系以及在体内通过逆转录病毒转染实验已表明NPM-ALK在细胞转化中具有直接作用。然而，在作为ALK嵌合体最常见靶点的T淋巴细胞中，尚无其致癌潜力的直接证据。在此，我们描述了一种新的淋巴瘤发生小鼠模型，其中人NPM-ALK转录靶向T细胞。NPM-ALK转基因（Tg）小鼠以预期的孟德尔分布出生，具有正常的淋巴器官，辅助性和抑制性T细胞数量及比例正常。然而，经过短暂的潜伏期后，所有NPM-ALK Tg小鼠都发生了恶性淋巴增殖性疾病（平均存活期为18周）。NPM-ALK Tg胸腺淋巴瘤表现出未成熟胸腺细胞的T细胞表型特征，并经常共表达表面CD30。一部分NPM-ALK Tg小鼠还发生了克隆性B细胞浆细胞瘤。这些肿瘤出现在外周淋巴器官（浆细胞瘤）或骨髓内，常导致外周神经病变和肢体麻痹。我们的NPM-ALK Tg小鼠是一种合适的模型，可用于剖析ALK介导的转化的分子机制，并在体内研究治疗人类ALCL的新治疗方法的疗效。
