Dasatinib therapy results in decreased B cell proliferation, splenomegaly, and tumor growth in a murine model of lymphoma expressing Myc and Epstein-Barr virus LMP2A.
Dasatinib therapy results in decreased B cell proliferation, splenomegaly, and tumor growth in a murine model of lymphoma expressing Myc and Epstein-Barr virus LMP2A.
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DOI：
10.1016/j.antiviral.2012.05.003
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发表时间：
2012-07
影响因子：
7.6
通讯作者：
Cen, Osman
中科院分区：
文献类型：
--
作者：
Dargart, Jamie L.;Fish, Kamonwan;Gordon, Leo I.;Longnecker, Richard;Cen, Osman
关键词：
EB病毒（Epstein-Barr virus，EBV）感染和潜伏期与鼻咽癌、霍奇金淋巴瘤、伯基特淋巴瘤和免疫缺陷相关的淋巴组织增生性疾病等恶性疾病有关。EB病毒编码的潜伏膜蛋白2A（LMP 2A）通过其SH 2结构域结合基序募集林恩和Syk激酶，并修饰它们的信号通路。LMP 2A转基因小鼠通过调节林恩激酶信号传导产生过度增殖的骨髓B细胞和未成熟的外周B细胞。LMP 2A/λ-MYC双转基因小鼠从8周龄开始出现脾肿大和颈部淋巴瘤。我们推断，用达沙替尼靶向表达LMP 2A的B细胞中的林恩将为EBV相关恶性肿瘤提供一种治疗选择。在这里，我们表明，达沙替尼抑制B细胞集落形成的LMP 2A转基因骨髓细胞，并逆转脾肿大和肿瘤生长的前肿瘤和EBV相关的伯基特淋巴瘤的同源肿瘤转移模型。我们的数据支持达沙替尼可能被证明是治疗EBV相关恶性肿瘤的有效治疗分子的想法。
Epstein-Barr virus (EBV) infection and latency has been associated with malignant diseases including nasopharyngeal carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and immune deficiency associated lymphoproliferative diseases. EBV-encoded latent membrane protein 2A (LMP2A) recruits Lyn and Syk kinases via its SH2-domain binding motifs, and modifies their signaling pathways. LMP2A transgenic mice develop hyperproliferative bone marrow B cells and immature peripheral B cells through modulation of Lyn kinase signaling. LMP2A/λ-MYC double transgenic mice develop splenomegaly and cervical lymphomas starting at 8 weeks of age. We reasoned that targeting Lyn in LMP2A-expressing B cells with dasatinib would provide a therapeutic option for EBV-associated malignancies. Here, we show that dasatinib inhibits B cell colony formation by LMP2A transgenic bone marrow cells, and reverses splenomegaly and tumor growth in both a pre-tumor and a syngeneic tumor transfer model of EBV-associated Burkitt lymphoma. Our data support the idea that dasatinib may prove to be an effective therapeutic molecule for the treatment of EBV-associated malignancies.
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