Mutational cooperativity in TET2-associated hematological malignancies.

TET2 相关血液恶性肿瘤中的突变协同性。

• 批准号: 10209454
• 负责人: Yun Huang
• 金额: $ 34.25万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209454
• 关键词: AKT Signaling Pathway; Advanced Development; Animal Model; Automobile Driving; Binding; Biological Assay; Biology; Blood Cells; CD4 Positive T Lymphocytes; Cancer Intervention; Caring; Cell physiology; Cells; Chemicals; Clinic; Clinical; DNA; DNA Modification Process; DNA Polymerase II; DNA-Directed RNA Polymerase; Dimensions; Dioxygenases; Disease; Dissection; Enzymes; Epigenetic Process; Etiology; Event; FOXO1A gene; Foundations; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Genotype; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Hematologic Neoplasms; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Hybrids; Impairment; Knock-in; Knowledge; Lead; Lesion; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Metabolism; Mission; Modification; Molecular; Molecular Target; Monomeric GTP-Binding Proteins; Mus; Mutation; Myelogenous; Natural Killer Cells; Oncogenic; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral; Phenotype; Phosphatidylinositols; Pilot Projects; Premalignant Cell; Prevention; Prognosis; RHOA gene; RNA; RNA Helicase; Research; Rodent Model; SETX gene; Sampling; Signal Pathway; Signal Transduction; Somatic Mutation; Structure; T-Cell Lymphoma; T-Lymphocyte; Testing; Therapeutic; Transcriptional Regulation; Transgenic Mice; Tumor Burden; United States National Institutes of Health; base; blood treatment; clinically relevant; effective therapy; epigenome; epigenome editing; epigenomics; exome sequencing; helicase; hematopoietic differentiation; innovation; insight; leukemia/lymphoma; lymphoid neoplasm; mouse model; new therapeutic target; novel; optogenetics; peripheral lymphoid organ; pre-clinical; premalignant; promoter; rho GTP-Binding Proteins; synergism; targeted treatment; tool; transcriptome sequencing; tumor; tumorigenesis

Project Summary/ Abstract Peripheral T cell lymphoma (PTCL) represents a group of aggressive blood cancers derived from mature T cells, and remains as a high unmet clinical need with poor prognosis and lack of standards of care and effective treatment. Recent exome sequencing in PTCL patients has unveiled a frequent co-occurrence of mutations in an epigenetic modifier (TET2) and a small GTPase (RHOA). This discovery heralds the advent of a molecular era in the dissection of novel pathogenic mechanisms underlying T cell lymphoma. The PI has shown that genetic depletion of murine Tet2 alone in blood cells causes biased differentiation of hematopoietic stem and progenitor cells (HSPCs) toward the myeloid lineage, but is insufficient to cause lymphoid neoplasms. A second hit, such as RHOA-G17V frequently found in PTCL, is required to promote full-blown malignancies. To meet the immediate need for animal models of PTCL, The PI has generated a genetically modified rodent model mimicking the PTCL-associated genotype with genetic lesions in both TET2 and RHOA. This transgenic mouse model is well suited to study PTCL because it developed T cell lymphoma in peripheral lymphoid organs and recapitulated hallmark phenotypes as seen in PTCL patients. These exciting findings laid a strong scientific foundation to hypothesize that: co-existing TET2 and RHOA mutations in CD4 T cells contribute to the pathogenesis of PTCLs by (i) impairing DNA hydroxymethylation and gene transcription to predispose T cells for pre-malignant status (Aim 1; with a mechanistic emphasis on R-loop accumulation and aberrant RNA polymerase II pausing in key genes involved in phosphoinositide metabolism), and (ii) disrupting the Rho GTPase signaling to abnormally activate pro-oncogenic pathways for malignant transformation (Aim 2; with a prioritized focus on the PI3K/Akt signaling). The team has presented compelling evidence in pilot studies that lends strong support to the central hypotheses and the feasibility of our approach. Technical innovations include a unique mouse model that reflects the PTCL-associated genotype and disease hallmarks, as well as a set of novel molecular tools tailored for precise epigenome mapping/editing and optogenetic control of small GTPase signaling. These tools allow the team to overcome a major impediment to studies of epigenotype- phenotype causal relations in pre-malignant and malignant T cells. This research is also conceptually innovative as it introduces a previously underappreciated dimension for studying the epigenetic regulatory mechanisms, as well as aberrant GTPase signaling, that drive lymphomagenesis. The proposed studies will likely illuminate how somatic mutations in epigenetic and GTPase signaling pathways cooperatively contribute to the initiation, transformation and progression of lymphoma. From a translational perspective, the findings may reveal novel molecular targets and pathways for therapies against lymphoma.

项目总结/摘要 外周T细胞淋巴瘤（PTCL）是一组来源于成熟T细胞的侵袭性血癌， 细胞，仍然是一个高度未满足的临床需求，预后不良，缺乏护理标准， 有效治疗。PTCL患者的最新外显子组测序揭示了PTCL患者的常见并发症， 表观遗传修饰因子（TET 2）和小GT3（RHOA）突变。这一发现预示着 一个解剖T细胞淋巴瘤潜在的新致病机制的分子时代。主要研究者有 表明血细胞中单独的鼠Tet 2的遗传缺失导致造血细胞的偏向分化， 干细胞和祖细胞（HSPC）向髓系分化，但不足以引起淋巴肿瘤。 第二次打击，如RHOA-G17 V经常在PTCL中发现，需要促进全面发展的恶性肿瘤。 为了满足PTCL动物模型的迫切需要，PI已经产生了一种转基因啮齿动物， 模型模拟在TET 2和RHOA中具有遗传损伤的PTCL相关基因型。该转基因 小鼠模型非常适合研究PTCL，因为它在外周淋巴细胞中发生了T细胞淋巴瘤。 器官和重现的标志表型，如在PTCL患者中所见。这些令人兴奋的发现奠定了强有力的 科学基础假设：CD 4 T细胞中共存的TET 2和RHOA突变有助于 PTCL的发病机制， （一） 损害DNA羟甲基化和基因转录以使T易感 癌前状态的细胞（目的1;强调R环积累和异常RNA的机制 聚合酶II在参与磷酸肌醇代谢的关键基因中暂停），和 （二） 扰乱了Rho GT3信号传导异常激活恶性转化的原癌途径（目的2;用 优先关注PI 3 K/Akt信号传导）。该团队在试点研究中提出了令人信服的证据， 强有力的支持中心假设和我们的方法的可行性。技术创新 包括反映PTCL相关基因型和疾病标志的独特小鼠模型，以及 一套新的分子工具，专门用于精确的表观基因组作图/编辑和小分子的光遗传学控制。 GT3信号。这些工具使研究小组克服了表观基因型研究的一个主要障碍- 表型因果关系在癌前和恶性T细胞。这项研究也是在概念上 创新，因为它引入了一个以前未被重视的维度，用于研究表观遗传调控 机制，以及异常的GT3信号传导，驱动淋巴瘤发生。拟议的研究将 可能阐明了表观遗传和GT3信号通路中的体细胞突变如何协同作用 与淋巴瘤的发生、转化和发展有关。从翻译的角度来看， 可能揭示新的分子靶点和治疗淋巴瘤的途径。