文章：

鉴定新型STAT5B突变并表征CD4+ T细胞大颗粒淋巴细胞白血病中的TCRβ特征

Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia

原文发布日期：2022-02-24

DOI: 10.1038/s41408-022-00630-8

类型: Article

开放获取: 是

英文摘要：

CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) is a rare subtype of T-LGLL with unknown etiology. In this study, we molecularly characterized a cohort of patients (n = 35) by studying their T-cell receptor (TCR) repertoire and the presence of somatic STAT5B mutations. In addition to the previously described gain-of-function mutations (N642H, Y665F, Q706L, S715F), we discovered six novel STAT5B mutations (Q220H, E433K, T628S, P658R, P702A, and V712E). Multiple STAT5B mutations were present in 22% (5/23) of STAT5B mutated CD4+ T-LGLL cases, either coexisting in one clone or in distinct clones. Patients with STAT5B mutations had increased lymphocyte and LGL counts when compared to STAT5B wild-type patients. TCRβ sequencing showed that, in addition to large LGL expansions, non-leukemic T cell repertoires were more clonal in CD4+ T-LGLL compared to healthy. Interestingly, 25% (15/59) of CD4+ T-LGLL clonotypes were found, albeit in much lower frequencies, in the non-leukemic CD4+ T cell repertoires of the CD4+ T-LGLL patients. Additionally, we further confirmed the previously reported clonal dominance of TRBV6-expressing clones in CD4+ T-LGLL. In conclusion, CD4+ T-LGLL patients have a typical TCR and mutation profile suggestive of aberrant antigen response underlying the disease.
 

摘要翻译： 

CD4+ T细胞大颗粒淋巴细胞白血病（T-LGLL）是一种病因未明的罕见T-LGLL亚型。本研究通过分析患者（n=35）的T细胞受体（TCR）库及体细胞STAT5B突变存在情况，对其进行了分子特征描述。除先前报道的功能获得性突变（N642H、Y665F、Q706L、S715F）外，我们发现了六种新型STAT5B突变（Q220H、E433K、T628S、P658R、P702A和V712E）。在STAT5B突变的CD4+ T-LGLL病例中，22%（5/23）存在多个STAT5B突变，这些突变可共存于一个克隆或不同克隆中。与STAT5B野生型患者相比，STAT5B突变患者的淋巴细胞和大颗粒淋巴细胞计数更高。TCRβ测序显示，CD4+ T-LGLL患者除存在大量LGL扩增外，其非白血病性T细胞库相较于健康人群更具克隆性。值得注意的是，在CD4+ T-LGLL患者的非白血病性CD4+ T细胞库中，25%（15/59）的CD4+ T-LGLL克隆型以更低频率存在。此外，我们进一步证实了先前报道的CD4+ T-LGLL中TRBV6表达克隆的克隆优势现象。总之，CD4+ T-LGLL患者具有典型的TCR和突变特征，提示该疾病存在异常的抗原反应基础。

原文链接：

Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia