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RECURRENT MUTATIONS IN EPIGENETIC REGULATORS, RHOA AND FYN KINASE IN PERIPHERAL T-CELL LYMPHOMAS
RECURRENT MUTATIONS IN EPIGENETIC REGULATORS, RHOA AND FYN KINASE IN PERIPHERAL T-CELL LYMPHOMAS
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机译:周围T细胞淋巴瘤的表观调节剂,Rhoa和Fyn激酶的递归突变
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摘要
Whole exome sequencing of 12 tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing identified new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DN-MT3A and IDH2 as well as a new highly prevalent RHOA p.Gly17Val (NM_001664) mutation present in 22/35 (67%) of angioimmunoblastic T-cell lymphomas (AITL) and in 8/44 (18%) not otherwise specified PTCL (PTCL NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated Guanine Exchange Factor (GEF) proteins. In addition, new and recurrent, genetic defects are described including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.
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机译:对12个正常肿瘤DNA对的全外显子组测序,RNAseq分析和靶向深度测序确定了PTCL转化中的新遗传改变。这些分析确定了TET2,DN-MT3A和IDH2中高度复发的表观遗传因子突变,以及在22/35(67%)的血管免疫母细胞性T细胞淋巴瘤(AITL)和在8/44(18%)中未另外指定的PTCL(PTCL NOS)样品。从机理上讲,RHOA A Gly17Val蛋白在生化和细胞分析中会干扰RHOA信号传导,这种作用可能是通过螯合活化的鸟嘌呤交换因子(GEF)蛋白来介导的。此外,还描述了新的和反复发生的遗传缺陷,包括与SRC信号有关的FYN,ATM,B2M和CD58中的突变,受损的DNA损伤反应以及在PTCL发病机理中逃避了免疫监视机制。
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