Activating STAT6 mutations in follicular lymphoma
Activating STAT6 mutations in follicular lymphoma
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DOI：
10.1182/blood-2014-06-582650
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发表时间：
2015-01-22
期刊：
影响因子：
20.3
通讯作者：
Malek, Sami N.
中科院分区：
文献类型：
--
作者：
Yildiz, Mehmet;Li, Hongxiu;Malek, Sami N.
滤泡性淋巴瘤（FL）是西方世界第二常见的非霍奇金淋巴瘤。FL细胞内在和细胞外在因素影响FL生物学和临床结果。为了进一步了解FL的遗传基础，我们对23例高度纯化的FL病例和1例转化的FL病例进行了全外显子组测序，并将结果扩展到总共114个FL。我们报告了11%的FL中转录因子STAT 6的复发性突变，并将STAT 6氨基酸残基419鉴定为新的STAT 6突变热点（p.419D/G，p.419D/A和p.419D/H）。FL相关的STAT 6突变是激活的，如在基于HEK 293 T细胞的转染/荧光素酶报告基因测定中增加的反式激活、在稳定的STAT 6转染的淋巴瘤细胞系中增强的白细胞介素-4（IL-4）诱导的靶基因激活以及在携带突变的STAT 6的原代FL B细胞中升高的STAT 6靶基因的基线表达水平所证明的。从机制上讲，FL相关的STAT 6突变促进了STAT 6的核驻留，独立于IL-4诱导的STAT 6-Y 641磷酸化。基于STAT 1-DNA复合物结构的STAT 6结构建模显示，大多数FL相关的STAT 6突变体位于STAT 6-DNA界面，可能促进增强的相互作用。遗传和功能数据相结合，加强了IL-4/JAK/STAT 6轴作为FL发病机制驱动因素的认识。
Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the Western world. FL cell-intrinsic and cell-extrinsic factors influence FL biology and clinical outcome. To further our understanding of the genetic basis of FL, we performed whole-exome sequencing of 23 highly purified FL cases and 1 transformed FL case and expanded findings to a combined total of 114 FLs. We report recurrent mutations in the transcription factor STAT6 in 11% of FLs and identified the STAT6 amino acid residue 419 as a novel STAT6 mutation hotspot (p.419D/G, p.419D/A, and p.419D/H). FL-associated STAT6 mutations were activating, as evidenced by increased transactivation in HEK293T cell-based transfection/luciferase reporter assays, heightened interleukin-4 (IL-4) -induced activation of target genes in stable STAT6 transfected lymphoma cell lines, and elevated baseline expression levels of STAT6 target genes in primary FL B cells harboringmutant STAT6. Mechanistically, FL-associated STAT6 mutations facilitated nuclear residency of STAT6, independent of IL-4-induced STAT6-Y641 phosphorylation. Structural modeling of STAT6 based on the structure of the STAT1-DNA complex revealed that most FL-associated STAT6 mutants locate to the STAT6-DNA interface, potentially facilitating heightened interactions. The genetic and functional data combined strengthen the recognition of the IL-4/JAK/STAT6 axis as a driver of FL pathogenesis.