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: 10600101
• 负责人: Yun Huang
• 金额: $ 33.52万
• 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/10600101
• 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 Separation; Cell physiology; Cells; Chemicals; Clinic; Clinical; DNA; DNA Modification Process; 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; Lesion; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant Neoplasms; Maps; Mature T-Lymphocyte; Mediating; Metabolism; Mission; Modification; Molecular; Molecular Target; Monomeric GTP-Binding Proteins; Mus; Mutation; Myelogenous; Natural Killer Cells; Oncogenic; PIK3CG gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral; Phenotype; Phosphatidylinositols; Pilot Projects; Polymerase; Premalignant Cell; Prevention; Prognosis; RHOA gene; RNA; RNA Helicase; RNA Polymerase II; Research; Rodent Model; 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; 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; 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.

项目摘要/摘要 周围T细胞淋巴瘤（PTCL）代表一组源自成熟T的侵袭性血液癌 细胞，并且仍然是高度未满足的临床需求，预后不良，缺乏护理标准和 有效的治疗。 PTCL患者最近的外显子组测序已揭示了经常出现的 表观遗传修饰剂（TET2）和小GTPase（RhoA）中的突变。这个发现预示了 在T细胞淋巴瘤下的新型致病机制解剖中的分子时代。 Pi具有 表明血细胞中单独的鼠TET2的遗传耗竭会导致造血的分化有偏差 茎和祖细胞（HSPC）朝向髓样谱系，但不足以引起淋巴性肿瘤。 促进成熟的恶性肿瘤需要第二次打击，例如在PTCL中经常发现的Rhoa-G17V。 为了满足PTCL动物模型的直接需求，PI产生了转基因的啮齿动物 模拟TET2和RHOA中遗传病变的PTCL相关基因型的模型。这个转基因 小鼠模型非常适合研究PTCL，因为它在周围淋巴样中发展了T细胞淋巴瘤 在PTCL患者中，器官和概括的标志性表型。这些令人兴奋的发现表现得很强烈 假设这一点的科学基础：CD4 T细胞中共存的TET2和RhoA突变有助于 PTCL的发病机理 （我） 损害DNA羟甲基化和基因转录至易感性T 细胞的恶性状态（AIM 1；具有机械强调R环的积累和异常RNA 聚合酶II暂停参与磷酸肌醇代谢的关键基因）和 （ii） 破坏Rho GTPase信号传导异常激活亲构途径以进行恶性转化（AIM 2；与A 优先关注PI3K/AKT信号传导）。该团队在试点研究中提出了令人信服的证据 对中央假设和我们方法的可行性提供了强有力的支持。技术创新 包括一个独特的小鼠模型，该模型反映了与PTCL相关的基因型和疾病标志，以及 针对精确的表观基因组映射/编辑和小遗传控制的新型分子工具集 GTPase信号传导。这些工具使团队能够克服对表观型的研究的重大障碍 - 恶性和恶性T细胞中的表型因果关系。这项研究在概念上也是 创新性，因为它引入了以前未经评价的研究表观遗传调节的维度 机理以及异常的GTPase信号传导，可驱动淋巴作用。拟议的研究将 可能阐明表观遗传和GTPase信号通路中的体细胞突变如何合作 淋巴瘤的起始，转化和进展。从转化的角度来看 可能揭示了针对淋巴瘤疗法的新型分子靶标和途径。