STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia
STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia
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DOI：
10.1182/blood-2012-06-435297
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发表时间：
2012-10-11
期刊：
影响因子：
20.3
通讯作者：
Maciejewski, Jaroslaw P.
中科院分区：
文献类型：
--
作者：
Jerez, Andres;Clemente, Michael J.;Maciejewski, Jaroslaw P.
慢性自然杀伤细胞增殖性疾病(CLPD-NKs)和T细胞大颗粒淋巴细胞白血病(T-LGL)是由自然杀伤细胞或细胞毒性T淋巴细胞(CTL)引起的克隆性淋巴增殖性疾病。我们通过直接测序、等位基因特异性聚合酶链式反应和基因芯片分析，研究了50例CLPD-NKs和120例T-LGL患者突变的分布和功能意义。在T和NK疾病中都存在STAT3基因突变：每种类型的疾病患者中约有三分之一携带这些突变。在编码Src同源2结构域的外显子21和20中发现了突变。突变患者的特征是有症状的疾病(75%)，有多次治疗的病史，以及STAT3激活和基因去调控的特定模式，包括STAT3激活的基因表达增加。其中许多特征也在野生型STAT3患者中发现，表明STAT3激活的其他机制可以在这些慢性淋巴增生性疾病中操作。在野生型和突变型病例中，用STAT3抑制剂治疗都会加速细胞凋亡。STAT3突变在大颗粒淋巴细胞中很常见，提示在NK和CTL起源的恶性慢性扩张中也存在类似的分子失调。STAT3突变可能区分真正的恶性淋巴增殖性T细胞和NK细胞和反应性扩张。(血。2012；120(15)：3048-3057)
Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pattern of STAT3 activation and gene deregulation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoproliferative disorders. Treatment with STAT3 inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a similar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions. (Blood. 2012; 120(15): 3048-3057)