The role of RHOA G17V mutation in peripheral t-cell lymphomas

 描述(由申请人提供)：外周T细胞淋巴瘤(PTCL)是一种非霍奇金淋巴瘤的异质性和缺乏了解的病理组，预后不良。目前对该病的遗传学和发病机制知之甚少，临床迫切需要更好的诊断工具、预后生物标志物和治疗靶点。最近，我们利用肿瘤-正常DNA对的全外显子组测序、RNAseq分析和候选基因的靶向深度测序的组合，在PTCL转化中发现了新的遗传变化。我们的数据发现了RHOA癌基因的高度重复突变，包括在近70%的血管免疫母细胞T细胞淋巴瘤(AITL)和近20%的PTCL(PTCL NOS)样本中存在的高度流行的RHOA G17V等位基因。我们的中心假设是，RHOA G17V突变作为RHOA信号的负调控因子，并作为PTCL的致癌驱动因素。本研究的目的是利用RhoA G17V诱导的小鼠淋巴瘤模型，确定RHOA G17V促进T细胞转化的机制和途径，并在体内分析该突变在AITL发病机制中的致癌作用。

 DESCRIPTION (provided by applicant): Peripheral T-cell lymphomas (PTCLs) constitute a heterogeneous and poorly understood pathological group of non-Hodgkin lymphomas associated with poor prognosis. Little is known on the genetics and mechanisms of this disease and better diagnostic tools, prognostic biomarkers and therapeutic targets are urgently needed in the clinic. Recently we have identified new genetic alterations in PTCL transformation by using a combination of whole exome sequencing of tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing of candidate genes. Our data identified highly recurrent mutations in the RHOA oncogene including a highly prevalent RHOA G17V allele present in almost 70% of angioimmunoblastic T- cell lymphomas (AITL) and almost 20% of PTCL not otherwise specified (PTCL NOS) samples. Our central hypothesis is that the RHOA G17V mutation acts as a negative regulator of RHOA signaling and as an oncogenic driver of PTCL. The goals of this research are to identify the mechanisms and pathways by which RHOA G17V contribute to T-cell transformation and to analyze the oncogenic effects of this mutation in the pathogenesis of AITL in vivo using a mouse model of RhoA G17V induced lymphoma.