Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.
Cancer Res. 2020 May 1;80(9):1875-1884. doi: 10.1158/0008-5472.CAN-19-2787. Epub 2020 Feb 27.
Recurrent hotspot (p.Gly17Val) mutations in encoding a small GTPase, together with loss-of-function mutations in encoding an epigenetic regulator, are genetic hallmarks of angioimmunoblastic T-cell lymphoma (AITL). Mice expressing the p.Gly17Val RHOA mutant on a -null background succumbed to AITL-like T-cell lymphomas due to deregulated T-cell receptor (TCR) signaling. Using these mice to investigate therapeutics for AITL, we found that dasatinib, a multikinase inhibitor prolonged their survival through inhibition of hyperactivated TCR signaling. A phase I clinical trial study of dasatinib monotherapy in 5 patients with relapsed/refractory AITL was performed. Dasatinib was started at a dose of 100 mg/body once a day and continued until days 10-78 (median day 58). All the evaluable patients achieved partial responses. Our findings suggest that AITL is highly dependent on TCR signaling and that dasatinib could be a promising candidate drug for AITL treatment. SIGNIFICANCE: Deregulated T-cell receptor signaling is a critical molecular event in angioimmunoblastic T-cell lymphoma and can be targeted with dasatinib.
编码小 GTP 酶的 RHOA 基因中的反复热点（p.Gly17Val）突变，以及编码表观遗传调节剂的基因中的功能丧失突变，是血管免疫母细胞性 T 细胞淋巴瘤（AITL）的遗传特征。在 -null 背景下表达 p.Gly17Val RHOA 突变的小鼠由于 T 细胞受体（TCR）信号的失调而患上 AITL 样 T 细胞淋巴瘤。使用这些小鼠来研究 AITL 的治疗方法，我们发现多激酶抑制剂达沙替尼通过抑制过度激活的 TCR 信号延长了它们的存活时间。对 5 例复发/难治性 AITL 患者进行了达沙替尼单药治疗的 I 期临床试验研究。达沙替尼起始剂量为 100mg/体，每天一次，持续至第 10-78 天（中位第 58 天）。所有可评估的患者均获得部分缓解。我们的研究结果表明，AITL 高度依赖 TCR 信号，达沙替尼可能是 AITL 治疗的一种有前途的候选药物。意义：失调的 T 细胞受体信号是血管免疫母细胞性 T 细胞淋巴瘤的一个关键分子事件，可以用达沙替尼靶向治疗。
