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

RHOA G17V 突变在外周 T 细胞淋巴瘤中的作用

• 批准号: 9298610
• 负责人: Teresa Palomero
• 金额: $ 36.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298610
• 关键词: Address; Adhesions; Affinity Chromatography; Alleles; Animal Model; B-Cell Neoplasm; Binding; Biochemical; Candidate Disease Gene; Cell Surface Receptors; Cell physiology; Cellular Morphology; Classification; Clinic; DNA; Data; Diagnostic; Disease; Family; GTP Binding; GTPase Gene; Genetic Predisposition to Disease; Genetic Transcription; Goals; Guanine Nucleotide Exchange Factors; Guanosine; Guanosine Triphosphate; Human; Immunoblastic Lymphadenopathy; Impairment; Knock-in Mouse; Link; Lymphoma; Mediating; Medical Genetics; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutation; Non-Hodgkin' s Lymphoma; Oncogenes; Oncogenic; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral; Prognostic Marker; Proteins; RHOA gene; Recurrence; Regulation; Research; Role; Sampling; Signal Transduction; Specific qualifier value; T-Cell Activation; T-Cell Lymphoma; T-Cell Transformation; T-Lymphocyte; Tumor Suppressor Genes; cell motility; cohort; deep sequencing; exome sequencing; genetic analysis; genetic approach; genomic tools; in vivo; insight; migration; mouse model; mutant; neoplastic cell; novel; outcome forecast; public health relevance; rho; therapeutic target; tool; transcriptome sequencing; tumor

 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.

 描述（由申请人提供）：外周 T 细胞淋巴瘤 (PTCL) 是一种异质性且知之甚少的非霍奇金淋巴瘤病理学组，与不良预后相关。人们对这种疾病的遗传学和机制知之甚少，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，我们通过结合肿瘤-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，发现了 PTCL 转化中的新遗传改变。我们的数据确定了 RHOA 癌基因中高度复发的突变，包括高度流行的 RHOA G17V 等位基因，存在于近 70% 的血管免疫母细胞 T 细胞淋巴瘤 (AITL) 和近 20% 的未另行指定的 PTCL (PTCL NOS) 样本中。我们的中心假设是 RHOA G17V 突变充当 RHOA 信号传导的负调节因子和 PTCL 的致癌驱动因素。本研究的目的是确定 RHOA G17V 促进 T 细胞转化的机制和途径，并使用 RhoA G17V 诱导淋巴瘤的小鼠模型分析该突变在体内 AITL 发病机制中的致癌作用。