文章：

大颗粒淋巴细胞白血病中影响STAT通路和T细胞活化的新体细胞突变

Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation

原文发布日期：2013-12-06

DOI: 10.1038/bcj.2013.65

类型: Original Article

开放获取: 是

英文摘要：

T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene, whereas STAT5 mutations are present in 2% of patients. In order to identify putative disease-causing genetic alterations in the remaining T-LGL patients, we performed exome sequencing from three STAT mutation-negative patients and validated the findings in 113 large granular lymphocytic (LGL) leukemia patients. On average, 11 CD8+ LGL leukemia cell-specific high-confidence nonsynonymous somatic mutations were discovered in each patient. Interestingly, all patients had at least one mutation that affects either directly the STAT3-pathway (such as PTPRT) or T-cell activation (BCL11B, SLIT2 and NRP1). In all three patients, the STAT3 pathway was activated when studied by RNA expression or pSTAT3 analysis. Screening of the remaining 113 LGL leukemia patients did not reveal additional patients with same mutations. These novel mutations are potentially biologically relevant and represent rare genetic triggers for T-LGL leukemia, and are associated with similar disease phenotype as observed in patients with mutations in the STAT3 gene.

摘要翻译： 

T细胞大颗粒淋巴细胞（T-LGL）白血病是一种以成熟CD3+CD8+细胞毒性T细胞扩增为特征的克隆性疾病，常与自身免疫性疾病和免疫介导的血细胞减少相关。我们近期研究发现，高达40%的T-LGL白血病患者携带STAT3基因突变，而STAT5基因突变仅见于2%的患者。为在其余未发现STAT基因突变的T-LGL白血病患者中鉴定潜在致病性遗传变异，我们对三例STAT突变阴性患者进行外显子组测序，并在113例大颗粒淋巴细胞（LGL）白血病患者中验证了相关发现。平均每位患者体内发现11个CD8+ LGL白血病细胞特异性的高可信度非同义体细胞突变。值得注意的是，所有患者均携带至少一个直接影响STAT3通路（如PTPRT）或T细胞活化（BCL11B、SLIT2和NRP1）的突变。通过RNA表达或pSTAT3分析证实，这三例患者的STAT3通路均被激活。在其余113例LGL白血病患者的筛查中，未发现相同突变的病例。这些新型突变可能具有生物学相关性，代表了T-LGL白血病的罕见遗传触发因素，并与STAT3基因突变患者中观察到的疾病表型相似。

原文链接：

Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation