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.

项目摘要/摘要十个易位（TET1，TET2和TET3）是α-酮戊二酸（αkg）和Fe2+依赖性DNA- 双氧酶是表观遗传景观的关键调节剂。这些酶逐渐氧化物5- 甲基胞嘧啶至5-羟基环胞嘧啶，再到5-甲基环胞嘧啶和5-羧基胞嘧啶在DNA中在大时尺度上有效转录至关重要的DNA脱甲基化。功能丧失 TET2突变（TET2MT）是MDS和相关血液学中最常见的致病性病变之一人类的恶性肿瘤。在所有疾病阶段和侵略性水平中都发现了TET2MT。此外，最近研究表明，在“健康”中经常发现体细胞2MT。存在芯片中的TET2MT意味着这是产生血液学疾病的早期事件。它也支持鼠研究结论TET2MT导致造血干细胞和祖细胞的扩张（HSPC）。早期的有缺陷克隆的演变中的事件是预防策略的合理目标，因为这种克隆在这种情况下阶段可能取决于这些事件。但是，它们在所有细胞中的存在也可以在疾病的晚期。例如，鼠类造血细胞中TET1和TE2的综合损失模型仅相对于单独的TET2损失而延长了寿命。此外，原则的证明也是得出的从IDH1/2MT患者的观察结果，这些新形态突变导致了A的产生弱TET抑制剂，2-羟基谷氨酸（2-HG），已知的二氧酶抑制剂。我们对IDH1/2MT的观察与TET2MT相互排斥，强烈支持我们的假设，即Tet抑制剂2-HG可防止 TET2MT克隆的演变。在髓样恶性肿瘤的细胞模型中进一步证实了该观察结果细胞并支持通过消除剩余的TET活性必不可少的综合杀伤力为有效的转录，用于TET-DIOXY酶缺乏TET2MT克隆中的增殖。我们的总体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二氧酶活性，以引起任何一种合成在TET2MT失活的情况下，致死性或谱系重定向。我们的目标是开发一种新颖的疗法通过评估TETI76作为临床前模型中TETI76作为靶向治疗的潜在用途，用于TET2MT MD的方法。更具体地说，我们的目标是：i）研究正常和恶性中TET抑制的机械后果体外造血。 ii）使用人和鼠类细胞在体外建立TETI化合物的作用模型和iii）表征TETI预防和治疗效率以及临床前的耐受性鼠模型。如果成功的话，我们的建议将导致一类新型的TET2MT相关造血的治疗剂疾病，也许还有其他二氧酶突变。这项工作也可能对癌症有影响在组蛋白脱甲基酶KDM6A中突变，该脱甲基酶KDM6A与TET2相似，并且经常在膀胱癌中突变。