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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• 作者：Jamie L. Dargart^a ; ^b ; ¹ ; ^{jamie.dargart@promedica.org} ; Kamonwan Fish^a ; ^{kamonwanfish2015@u.northwestern.edu} ; Leo I. Gordon^c ; ^{l-gordon@northwestern.edu} ; Richard Longnecker^a ; ^{r-longnecker@northwestern.edu} ; Osman Cen^a ; ^{o-cen@northwestern.edu}
• 关键词：BCR ; B cell receptor ; Das ; dasatinib ; a small molecule inhibitor of Src and Abl kinases ; EBV ; Epstein-Barr virus ; 位-MYC ; transgenic mice expressing MYC under the regulatory DNA sequence of immunoglobulin 位 gene ; LMP2A ; EBV-encoded latent membrane protei
• 刊名：Antiviral Research
• 出版年：2012
• 期刊代码：7_01663542
• 类别：imm
• 出版时间：July, 2012
• 卷：95
• 期：1
• 页码：49-56
• 文件大小：714 K

摘要

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/位-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.