IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma
IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma
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DOI：
10.1182/blood-2015-05-644591
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发表时间：
2015-10-08
期刊：
影响因子：
20.3
通讯作者：
Chan, Wing C.
中科院分区：
文献类型：
--
作者：
Wang, Chao;McKeithan, Timothy W.;Chan, Wing C.
血管免疫母细胞T细胞淋巴瘤(AITL)是外周T细胞淋巴瘤(PTCL)的常见亚型，预后不良。我们对92例PTCL进行了靶向重测序，发现了影响RHOA、TET2、DNMT3A和异柠檬酸脱氢酶2(IDH2)的频繁突变。虽然IDH2突变主要局限于AITL，但其他3种突变也可在其他类型的PTCL中发现，尽管频率较低。这些发现表明表观遗传调控在AITL的发病机制中起着关键作用。然而，这些突变引起的表观遗传学改变及其在AITL发病机制中的作用仍然很大程度上是未知的。我们将AITL的突变状态与基因表达和全球DNA甲基化变化相关联。值得注意的是，具有IDH2(R172)突变的AITL病例表现出明显的基因表达特征，其特征是与T-H1分化相关的基因(如STAT1和IFNG)下调，以及白介素12诱导的基因特征显著丰富。IDH2(R172K)在Jurkat细胞系和CD4(+)T细胞中的异位表达导致2-羟基戊二酸、组蛋白-3赖氨酸甲基化和5-甲基胞嘧啶水平显著增加，5-羟甲基胞嘧啶水平降低。相应地，IDH2突变的临床样本显示H3K27me3和基因启动子DNA高甲基化显著增加。基因表达和启动子甲基化的综合分析显示，与T细胞受体信号和T细胞分化有关的基因重复高甲基化，可能与AITL的淋巴肿大有关。
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2(R172) mutations demonstrated a distinct gene expression signature characterized by down-regulation of genes associated with T-H1 differentiation (eg, STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2(R172K) in the Jurkat cell line andCD4(+) T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysinemethylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2 mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.