Targeting TET DNA Dioxygenases as Therapeutic Principle in Myeloid Neoplasms

靶向 TET DNA 双加氧酶作为髓系肿瘤的治疗原则

基本信息

批准号：
10317562
负责人：
Babal K Jha
金额：
$ 60.83万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317562
关键词：
Affect Agreement Ascorbic Acid Biochemical Biological Biological Assay Bone Marrow CD34 gene Cardiovascular Diseases Cell Line Cell Lineage Cell Maintenance Cell model Cells Clinical Code CpG Islands DNA DNMT3a Data Development Dioxygenases Disease Dysmyelopoietic Syndromes Elderly Enhancers Enzymes Epigenetic Process Event Evolution Gatekeeping Generations Genes Genetic Genetic Transcription Genomics Goals Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Human Human Cell Line Human body In Vitro Investigation Knock-out Lead Lesion Libraries Life Malignant - descriptor Malignant Neoplasms Malignant neoplasm of urinary bladder Messenger RNA Methylation Modeling Modification Molecular Morphology Mus Mutate Mutation Myelogenous Myeloid Cells Myeloproliferative disease Neoplasms Oxides Pathogenicity Patients Pharmacology Phenotype Positioning Attribute Pre-Clinical Model Prevention strategy Production Residual state Site-Directed Mutagenesis Somatic Mutation Specificity Structure Sum Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Transcriptional Regulation Transplantation Treatment Efficacy Work alpha ketoglutarate cancer cell cohort demethylation design diagnostic biomarker enantiomer genetic manipulation high risk histone demethylase improved in vivo in vivo Model inhibitor/antagonist insight knock-down leukemia loss of function loss of function mutation mouse model mutant mutational status neoplastic cell novel novel therapeutic intervention novel therapeutics oxidation pre-clinical preclinical development preclinical trial predict responsiveness prevent programs promoter response small molecule targeted treatment therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT Ten Eleven Translocation (TET1, TET2 and TET3) are α-ketoglutarate (αKG) and Fe2+ dependent DNA- dioxygenases that is a key regulator of epigenetic landscape. These enzymes progressively oxidize 5- methylcytosine to 5-hydroxymethylcytosine and further to 5-formylcytosine and 5-carboxylcytosine in DNA culminating into DNA demethylation essential for efficient transcription over large time scales. Loss-of-function TET2 mutations (TET2MT), is one of the most frequent pathogenic lesion in MDS and related hematologic malignancies in humans. TET2MT are found in all disease stages and levels of aggressiveness. In addition, recent studies have demonstrated that somatic TET2MT are very frequently found in “healthy” elderly. The presence of TET2MT in CHIP implies that it is an early event in the creation of hematologic disorders. It also supports murine study conclusions that TET2MT cause expansions of hematopoietic stem and progenitor cells (HSPC). Early events in the evolution of defective clones are rational targets for preventative strategies since clones in such stages are likely to be dependent on these events. Their presence in all cells can, however, also be exploited in late stages of the disease. For example, the combined loss of TET1 and TE2 in hematopoietic cells in murine models extends life substantially relative to TET2 loss alone. In addition, the proof of principle is also derived from observation in patients with IDH1/2MT whereby, these neomorphic mutations lead to the production of a weak TET inhibitor, 2-hydroxyglutyrate (2-HG), known inhibitor of dioxygenases. Our observations that IDH1/2MT are mutually exclusive with TET2MT, strongly supports our hypotheses that the TET inhibitor, 2-HG, prevents evolution of TET2MT clones. This observation was further substantiated in a cellular model of myeloid malignant cells and supports that synthetic lethality can be achieved through elimination of remaining TET-activity essential for efficient transcription for proliferation in TET-dioxygenase deficient TET2MT clones. Our overarching hypothesis is that rationally designed and synthesized small molecules TETi76 can be utilized to impede compensatory TET dioxygenase activity originating from TET3 and TET1, to cause either synthetic lethality or lineage redirection in cases with TET2MT inactivation. Our goal is to develop a novel therapeutic approach for TET2MT MDS by evaluating the potential use of TETi76 as targeted treatments in preclinical models. More specifically, we aim to: i) Study the mechanistic consequences of TET inhibition in normal and malignant hematopoiesis in vitro. ii) Establish the effects of TETi compounds in vitro using human and murine cellular models and iii) Characterize TETi preventative and therapeutic efficacy as well as tolerability in pre-clinical murine models. Our proposal, if successful, will lead to a novel class of therapeutic agents for TET2MT associated hematopoietic disorders, and perhaps also other dioxygenase mutations. This work could also have implications for cancers mutated in histone demethylase KDM6A, which is similar to TET2 and frequently mutated in bladder cancer.

项目概要/摘要十十一易位（TET1、TET2 和 TET3）是 α-酮戊二酸 (αKG) 和 Fe2+ 依赖性 DNA- 双加氧酶是表观遗传景观的关键调节剂，这些酶逐渐氧化 5-。 DNA 中的甲基胞嘧啶转化为 5-羟甲基胞嘧啶，并进一步转化为 5-甲酰基胞嘧啶和 5-羧基胞嘧啶最终导致 DNA 去甲基化，这是长时间内有效转录所必需的。 TET2突变（TET2MT）是MDS和相关血液学中最常见的致病性病变之一 TET2MT 存在于人类的所有疾病阶段和侵袭性水平。研究表明，体细胞 TET2MT 在“健康”老年人中非常常见。 CHIP 中的 TET2MT 表明它是造成血液系统疾病的早期事件。它也支持小鼠。研究结论是 TET2MT 会导致造血干细胞和祖细胞 (HSPC) 扩增。有缺陷的克隆进化过程中的事件是预防策略的合理目标，因为此类克隆然而，它们在所有细胞中的存在也可以被利用。例如，小鼠造血细胞中 TET1 和 TE2 联合缺失。相对于单独的 TET2 损失，模型大大延长了寿命。此外，还得出了原理证明。根据对 IDH1/2MT 患者的观察，这些新形态突变导致产生弱 TET 抑制剂，2-羟基戊二酸 (2-HG)，已知的双加氧酶抑制剂。我们的观察结果是 IDH1/2MT。与 TET2MT 相互排斥，强烈支持我们的假设，即 TET 抑制剂 2-HG 可以预防 TET2MT 克隆的进化在骨髓恶性细胞模型中进一步证实了这一观察结果。细胞并支持合成致死可以通过消除剩余的 TET 活性来实现用于在 TET 双加氧酶缺陷的 TET2MT 克隆中有效转录增殖。我们的首要假设是，可以利用合理设计和合成的小分子 TETi76 阻碍源自 TET3 和 TET1 的补偿性 TET 双加氧酶活性，导致合成 TET2MT 失活病例的致死率或谱系重定向我们的目标是开发一种新的治疗方法。通过评估 TETi76 作为临床前模型中靶向治疗的潜在用途，研究 TET2MT MDS 的方法。更具体地说，我们的目标是： i) 研究正常和恶性细胞中 TET 抑制的机制后果体外造血作用 ii) 使用人和小鼠细胞建立 TETi 化合物的体外作用。模型和 iii) 表征临床前的预防和治疗功效以及耐受性小鼠模型。我们的建议如果成功，将产生一类新型 TET2MT 相关造血治疗药物疾病，或许还有其他双加氧酶突变，这项工作也可能对癌症产生影响。组蛋白去甲基化酶 KDM6A 发生突变，该酶与 TET2 相似，在膀胱癌中经常发生突变。