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）是一种异质性和知之甚少的非霍奇金淋巴瘤病理组，预后不良。目前对该病的遗传学和发病机制知之甚少，临床上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，我们通过使用肿瘤-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转化中鉴定了新的遗传改变。我们的数据确定了RHOA癌基因中的高度复发性突变，包括在几乎70%的血管免疫母细胞性T细胞淋巴瘤（AITL）和几乎20%的PTCL未另外说明（PTCL NOS）样本中存在的高度流行的RHOA G17 V等位基因。我们的中心假设是RHOA G17 V突变作为RHOA信号传导的负调节因子和PTCL的致癌驱动因子。本研究的目的是确定RHOA G17 V促进T细胞转化的机制和途径，并使用RhoA G17 V诱导的淋巴瘤小鼠模型分析该突变在体内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.