Mechanistic Determinants of Follicular-Helper T-cell Lymphomagenesis

滤泡辅助 T 细胞淋巴瘤发生的机制决定因素

• 批准号: 10166804
• 负责人: SAMUEL YAO-MING NG
• 金额: $ 25.06万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166804
• 关键词: Address; Advisory Committees; Affect; Antigen Receptors; B-Cell NonHodgkins Lymphoma; Binding; Biochemical; Biology; Cell Line; Cellular biology; Communities; Computational Biology; Coupled; CpG Islands; Cytosine; DNA; Dana-Farber Cancer Institute; Defect; Development; Development Plans; Disease; Dominant Genetic Conditions; Dominant-Negative Mutation; Environment; Epigenetic Process; Follicular Lymphoma; Functional disorder; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Genome; Goals; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Helper-Inducer T-Lymphocyte; Heterogeneity; Inferior; International; Knowledge; Laboratories; Lymphoma; Lymphoma cell; Lymphomagenesis; Malignant - descriptor; Mediating; Methylation; Modeling; Modification; Molecular; Molecular Target; Monomeric GTP-Binding Proteins; Mus; Mutate; Mutation; Nodal; Non-Hodgkin' s Lymphoma; Outcome; Pathway interactions; Patients; Peripheral; Phosphatidylinositols; Phosphotransferases; Physicians; Positioning Attribute; Primary Neoplasm; Property; Protein Family; Proteins; Proteomics; RHOA gene; Receptor Signaling; Recurrence; Research; Research Personnel; Sampling; Scientist; Signal Pathway; Signal Transduction; Sirolimus; Structure; Survival Rate; T-Cell Lymphoma; T-Cell Receptor; T-Cell Transformation; T-Lymphocyte; Testing; Training; Translating; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; career; genetic analysis; genetic regulatory protein; genomic locus; knock-down; loss of function; loss of function mutation; mutant; novel; novel strategies; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; receptor; rho; targeted treatment; tool; translational cancer research; tumor

Project Summary/Abstract Outcomes among patients with Nodal Lymphomas of Follicular-Helper T cell (TFH) origin are poor, with overall survival rates of <35% at 5 years. These lymphomas are characterized by the recurrent hotspot RHOA G17V and TET2 loss-of-function (LOF) mutations. The causative molecular contributions of these mutations to TFH lymphomagenesis remain undefined. Rho family proteins are molecular switches that are active when bound to GTP and inactive when bound to GDP. The G17V mutation locks RhoA in an inactive state that has dominant negative and likely neomorphic function through sequestration of multi-substrate binding partners. TET2 LOF mutations are predicted to cause increased 5' methylation (5-mC) and decreased 5' hydroxymethylation (5-hmC) of DNA cytosines, both of which are predicted to result in diminished expression from affected genetic loci. These inactivating properties make these mutations difficult to target. Recently we and others have determined that RHOA G17V expression causes increased signaling through the Akt/mTOR pathway during T-cell receptor (TCR) and co-stimulatory pathway stimulation. We hypothesize that RhoAG17V-mediated disruption of signaling through multi-substrate small GTPase regulatory proteins combined with gene expression and epigenetic aberrancies caused by TET2 loss drive lymphomagenesis in T cells. We will test this with two specific aims. 1. Determine the molecular intermediaries of RhoA G17V-mediated TCR and co-stimulatory receptor dysfunction. We will determine direct binding partners of RhoA G17V and define how they modulate TCR and co-stimulatory pathways to promote lymphomagenesis. 2. Determine the epigenetic and transcriptional aberrancies mediated by TET2 loss in T cells. We will use a unique Nodal TFH lymphoma cell line to define the epigenetic modifications associated with TET2 loss and to determine whether genes that are silenced by these mutations can act as tumor suppressors. There are no current therapies that directly target these mutations, and thus, these studies serve an unmet need for these diseases. Dr. Ng has outlined a five-year development plan to achieve his goal of becoming an independent investigator in translational cancer research. He has assembled an advisory committee of internationally recognized experts in antigen-receptor signaling, malignant T-cell, and lymphoma biology. He has enlisted collaborators who are experts in epigenetics and computational biology to provide experimental advice and for specific training in the field. Dana- Farber Cancer Institute is the ideal environment for completion of his scientific and career goals given its outstanding research community and substantial record for training independent physician- scientists.

项目摘要/摘要 卵泡螺旋T细胞（TFH）起源的淋巴结淋巴瘤患者的结局很差，有 5年时的总生存率<35％。这些淋巴瘤的特征是复发热点 RhoA G17V和TET2功能丧失（LOF）突变。致病分子贡献 这些对TFH淋巴作用的突变仍然不确定。 Rho家族蛋白是分子 当与GDP绑定时，当绑定到GTP时活跃的开关与GDP绑定。 G17V突变 将Rhoa锁定在不活跃的状态 隔离多材料结合伙伴的固相。预测TET2 LOF突变会导致 增加了5'甲基化（5-MC），并降低5'羟甲基（5-HMC）的DNA胞质 其中预测会导致受影响的遗传基因座的表达降低。这些灭活 属性使这些突变难以靶向。最近，我们和其他人确定Rhoa G17V表达在T细胞受体期间通过AKT/MTOR途径引起信号增加 （TCR）和共刺激途径刺激。我们假设RhoAG17V介导的破坏 通过多毛基板小GTPase调节蛋白与基因表达结合的信号传导 TET2损失驱动T细胞中淋巴作用引起的表观遗传差。我们将测试这个 有两个具体的目标。 1。确定RhoA G17V介导的TCR和 共刺激受体功能障碍。我们将确定Rhoa G17V的直接约束伙伴和 定义它们如何调节TCR和共刺激途径以促进淋巴作用。 2。 确定T细胞中TET2损失介导的表观遗传和转录差。我们将 使用独特的淋巴结TFH淋巴瘤细胞系来定义与TET2相关的表观遗传修饰 损失并确定这些突变沉默的基因是否可以充当肿瘤 抑制器。目前没有直接针对这些突变的疗法，因此 研究满足了这些疾病的需求。 NG博士概述了一项为期五年的发展计划 实现他成为转化癌症研究的独立研究者的目标。他有 组建了一个国际认可的抗原受体信号专家的咨询委员会， 恶性T细胞和淋巴瘤生物学。他邀请了表观遗传学专家的合作者 和计算生物学，以提供实验建议并在现场进行特定培训。 dana- Farber癌症研究所是完成其科学和职业目标的理想环境 其杰出的研究社区和培训独立医师的大量记录 -​​ 科学家。