Zeng Longhui, Zhang Xinyan, Xiong Yiwei, Sato Kazuki, Hajicek Nicole, Kogure Yasunori, Kataoka Keisuke, Ogawa Seishi, Sondek John, Su Xiaolei
Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA.
Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
EMBO Rep. 2025 Aug 12. doi: 10.1038/s44319-025-00546-x.
Phospholipase C gamma 1 (PLCG1) has been identified as the most frequently mutated gene in adult T-cell leukemia/lymphoma, suggesting a critical function of PLCG1 in driving T cell activation. However, it remains unclear how these mutations regulate T cell physiology and pathology. Here, we investigate three common leukemia/lymphoma-associated mutations (R48W, S345F, and D1165H). We discover that these mutations induce hyperactive T cell signaling and cause pro-survival phenotypes. PLCG1 mutants enhance LAT condensation, calcium influx, and ERK activation. They also promote T cell proliferation, upregulate cell adhesion molecules, induce cell aggregation, and confer resistance to Vorinostat, an FDA-approved drug for cutaneous T-cell lymphoma. The resistance depends on ERK signaling and can be reversed with an ERK inhibitor. Interestingly, PLCG1 mutants also induce bystander drug resistance in nearby cells expressing wild-type PLCG1. Mechanistically, alpha smooth muscle actin, which is specifically induced by PLCG1 mutants, directly binds PLCG1 to promote its activation. These results demonstrate that hyperactive PLCG1 promotes T cell survival and drug resistance by inducing non-canonical signaling.
磷脂酶Cγ1（PLCG1）已被确定为成人T细胞白血病/淋巴瘤中最常发生突变的基因，这表明PLCG1在驱动T细胞活化中具有关键作用。然而，这些突变如何调节T细胞的生理和病理状态仍不清楚。在此，我们研究了三种常见的白血病/淋巴瘤相关突变（R48W、S345F和D1165H）。我们发现这些突变会诱导T细胞信号过度活跃并导致促生存表型。PLCG1突变体增强LAT聚集、钙内流和ERK激活。它们还促进T细胞增殖、上调细胞粘附分子、诱导细胞聚集，并赋予对伏立诺他（一种美国食品药品监督管理局批准用于皮肤T细胞淋巴瘤的药物）的抗性。这种抗性依赖于ERK信号传导，并且可以用ERK抑制剂逆转。有趣的是，PLCG1突变体还会在表达野生型PLCG1的附近细胞中诱导旁观者耐药性。从机制上讲，由PLCG1突变体特异性诱导的α平滑肌肌动蛋白直接结合PLCG1以促进其激活。这些结果表明，过度活跃的PLCG1通过诱导非经典信号传导促进T细胞存活和耐药性。
