The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ-TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling
The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ-TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling
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DOI：
10.1182/blood-2010-03-275180
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发表时间：
2010-12-02
期刊：
影响因子：
20.3
通讯作者：
Efremov, Dimitar G.
中科院分区：
文献类型：
--
作者：
Suljagic, Mirza;Longo, Pablo G.;Efremov, Dimitar G.
抑制抗原依赖性B细胞受体（BCR）信号传导被认为是慢性淋巴细胞白血病（CLL）的一种有前途的治疗方法，但仍缺乏支持这一观点的体内实验证据。我们现在已经研究了用选择性Syk抑制剂fostamatinib disodium（R788）抑制BCR信号传导是否会影响在CLL的E mu-TCL 1转基因小鼠模型中发展的白血病的生长。与人类CLL相似，这些白血病表达定型的BCR，其与暴露在衰老或凋亡细胞表面上的自身抗原反应，表明它们是抗原驱动的。我们表明，R788有效地抑制BCR信号在体内，导致恶性B细胞的增殖和生存减少，并显着延长治疗动物的生存。R788的生长抑制作用发生，尽管在体外的细胞毒性作用相对温和，是独立的基础Syk活性，表明R788的功能主要是通过抑制抗原依赖性BCR信号。重要的是，发现R788的作用对恶性克隆具有选择性，因为没有观察到正常B淋巴细胞产生的干扰。总的来说，这些数据为R788在CLL中的临床试验提供了进一步的理论基础，并确立了BCR信号通路作为这种疾病的重要治疗靶点。（血。2010;116（23）：4894-4905）
Inhibition of antigen-dependent B-cell receptor (BCR) signaling is considered a promising therapeutic approach in chronic lymphocytic leukemia (CLL), but experimental in vivo evidence to support this view is still lacking. We have now investigated whether inhibition of BCR signaling with the selective Syk inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias that develop in the E mu-TCL1 transgenic mouse model of CLL. Similarly to human CLL, these leukemias express stereotyped BCRs that react with autoantigens exposed on the surface of senescent or apoptotic cells, suggesting that they are antigen driven. We show that R788 effectively inhibits BCR signaling in vivo, resulting in reduced proliferation and survival of the malignant B cells and significantly prolonged survival of the treated animals. The growth-inhibitory effect of R788 occurs despite the relatively modest cytotoxic effect in vitro and is independent of basal Syk activity, suggesting that R788 functions primarily by inhibiting antigen-dependent BCR signals. Importantly, the effect of R788 was found to be selective for the malignant clones, as no disturbance in the production of normal B lymphocytes was observed. Collectively, these data provide further rationale for clinical trials with R788 in CLL and establish the BCR-signaling pathway as an important therapeutic target in this disease. (Blood. 2010;116(23):4894-4905)