{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:17:19Z","timestamp":1779167839931,"version":"3.51.4"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T00:00:00Z","timestamp":1663891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>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&amp;gt;G (p.<jats:italic>Tyr82Cys<\/jats:italic>) and c.265C&amp;gt;T(p.<jats:italic>Arg89Cys)<\/jats:italic> variations in a single familial case with EBV-positive peripheral T-cell lymphoma(NOS),accompanied HLH;we also detected <jats:italic>Tyr82Cys<\/jats:italic> 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 <jats:italic>Tyr82Cys<\/jats:italic> and <jats:italic>Arg89Cys<\/jats:italic> mutations is a loss-of function mutations on TIM-3,resulting in a weakened TIM-3 signaling. Our results suggest <jats:italic>Tyr82Cys<\/jats:italic> 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.<\/jats:p>","DOI":"10.3389\/fonc.2022.870676","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T13:28:36Z","timestamp":1663939716000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A novel germline HAVCR2 (TIM-3) compound heterozygous mutation is related to hemophagocytic lymphohistiocytic syndrome in EBV-positive peripheral T-cell lymphoma (NOS) with down-regulated TIM-3 signaling"],"prefix":"10.3389","volume":"12","author":[{"given":"Yang","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoyu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jieping","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiying","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunhong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honglin","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunxiao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhao","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangsen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-04-087288","article-title":"EORTC 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