Vitamin C-induzierte DNA-Demethylierung als Präventivtherapie für Leukämie

维生素 C 诱导的 DNA 去甲基化作为白血病的预防疗法

• 批准号: 446251518
• 负责人: Dr. Sarah Grasedieck
• 金额: --
• 依托单位: Michael Smith Laboratories
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/446251518?language=en
• 关键词: Vitamin; induzierte; DNA; Demethylierung; als

Mutations in genes that either encode or affect the function of epigenetic regulators are frequent early events in aging-related clonal hematopoiesis and were found to precede leukemic transformation in longitudinal patient studies. Correspondingly, a large proportion of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients show genome-wide alterations in chromatin methylation. Recent work, including the host lab’s, has identified gains in cytosine methylation at enhancer elements in response to isocitrate dehydrogenase (IDH) and ten-eleven translocation dioxygenase (TET) mutations to directly affect myeloid differentiation in murine models. The host lab showed that vitamin C, which activates a set of enzymes that catalyze genome demethylation, can resolve enhancer hypermethylation and thereby re-initiate expression of key myeloid genes in vitro. These findings suggest that TET and IDH mutations actively contribute to the block of differentiation that is a hallmark of AML and that this can be readily reversed by a known, non-toxic molecule. In this proposal, I suggest to explore the efficacy of vitamin C both individually and in combination with other demethylating therapies in pre-clinical in vivo settings. Further, considering that TET and IDH mutations can be detected in individuals prior to disease outbreak using routine diagnostic techniques, I propose to explore the potential of high dose vitamin C supplementation to restore cytosine methylation homeostasis in affected cells with the ultimate goal to delay or prevent the transformation towards myeloid malignancy.

编码或影响表观遗传调控因子功能的基因突变是衰老相关克隆造血中常见的早期事件，在纵向患者研究中发现，突变发生在白血病转化之前。相应地，很大比例的骨髓增生异常综合征（MDS）和急性髓性白血病（AML）患者在染色质甲基化方面表现出全基因组的改变。最近的工作，包括宿主实验室的工作，已经确定了在响应异柠檬酸脱氢酶（IDH）和10 - 11易位双加氧酶（TET）突变的增强子元件上的胞嘧啶甲基化的增益，直接影响小鼠模型中的骨髓分化。宿主实验室表明，维生素C激活一组催化基因组去甲基化的酶，可以解决增强子超甲基化，从而在体外重新启动关键髓系基因的表达。这些发现表明TET和IDH突变积极地促进了分化的阻断，这是AML的一个标志，这可以很容易地被一种已知的无毒分子逆转。在本提案中，我建议在临床前体内环境中探索维生素C单独或与其他去甲基化疗法联合使用的功效。此外，考虑到TET和IDH突变可以在疾病爆发前使用常规诊断技术在个体中检测到，我建议探索高剂量维生素C补充的潜力，以恢复受影响细胞中胞嘧啶甲基化稳态，最终目的是延迟或阻止向髓系恶性肿瘤的转变。