Zhang Yang, Wang Zhihua, Hu Guoyu, Li Jieping, Chen Yongheng, Jiang Yi, Zhong Haiying, Liu Xianling, Hu Chunhong, Peng Honglin, Xu Yunxiao, Cheng Zhao, Zhang Guangsen
Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China.
Front Oncol. 2022 Sep 23;12:870676. doi: 10.3389/fonc.2022.870676. eCollection 2022.
Recently, it have been reported that Hepatitis A Virus-Cellular Receptor 2(HAVCR2,encoding T-cell immunoglobulin and Mucin-Containing Protein 3[TIM3]) mutations are associated with severe hemophagocytic syndrome(HLH) in subcutaneous panniculitis-like T-cell lymphoma(SPTCL),and there are also frequent mutations in sporadic SPTCL, suggesting the individuals harboring HAVCR2(TIM-3) germline mutations are highly susceptible to familial or sporadic SPTCL. Here, we identify a novel germline compound heterozygous mutation of TIM-3 gene,c.245A>G (p.) and c.265C>T(p. variations in a single familial case with EBV-positive peripheral T-cell lymphoma(NOS),accompanied HLH;we also detected germline mutation in TIM-3 gene in one sporadic patient with cutaneous T cell lymphoma. We screened the distributive frequencies for TIM-3 mutations in healthy controls(n=87), B-(n=79) or T-cell lymphoma(n=25) not SPTCL, and the results showed that the mutation was found in two out of 25 patients with T-cell lymphoma but was not detected in 79 patients with B-cell lymphoma nor in a group of 87 controls. The mRNA expression of TIM-3 on primary cells and transfected HEK293 cells reduced significantly, indicating and mutations is a loss-of function mutations on TIM-3,resulting in a weakened TIM-3 signaling. Our results suggest TIM-3 germline mutations are not only limited in SPTCL, and also occurred in other types of T-cell lymphoma, especially complicated HLH. TIM-3 mutations may be an predisposing factor for T-cell lymphoma and molecular marker for auxiliary diagnosis in T cell lymphoma,especially complicated with HLH.
最近，有报道称甲型肝炎病毒细胞受体2（HAVCR2，编码T细胞免疫球蛋白和含粘蛋白蛋白3[TIM3]）突变与皮下脂膜炎样T细胞淋巴瘤（SPTCL）中的严重噬血细胞综合征（HLH）相关，并且散发性SPTCL中也存在频繁突变，这表明携带HAVCR2（TIM-3）种系突变的个体对家族性或散发性SPTCL高度易感。在此，我们在1例伴有HLH的EBV阳性外周T细胞淋巴瘤（NOS）家族性病例中鉴定出一种新的TIM-3基因种系复合杂合突变，即c.245A>G（p.）和c.265C>T（p.）；我们还在1例皮肤T细胞淋巴瘤散发性患者中检测到TIM-3基因的种系突变。我们筛查了健康对照（n = 87）、非SPTCL的B细胞淋巴瘤（n = 79）或T细胞淋巴瘤（n = 25）中TIM-3突变的分布频率，结果显示在25例T细胞淋巴瘤患者中有2例发现了该突变，但在79例B细胞淋巴瘤患者和87例对照组中均未检测到。原发性细胞和转染的HEK293细胞上TIM-3的mRNA表达显著降低，表明 和 突变是TIM-3的功能丧失突变，导致TIM-3信号减弱。我们的结果表明，TIM-3种系突变不仅局限于SPTCL，也发生在其他类型的T细胞淋巴瘤中，尤其是并发HLH的情况。TIM-3突变可能是T细胞淋巴瘤的一个易感因素以及T细胞淋巴瘤尤其是并发HLH时辅助诊断的分子标志物。
