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节因子功能的基因突变是衰老相关克隆造血过程中常见的早期事件，并且在纵向患者研究中发现先于白血病转化。相应地，很大一部分骨髓增生异常综合征（MDS）和急性髓系白血病（AML）患者表现出全基因组染色质甲基化改变。最近的工作，包括宿主实验室的工作，已经确定了响应异柠檬酸脱氢酶（IDH）和十十一易位双加氧酶（TET）突变的增强子元件胞嘧啶甲基化的增益，从而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 可以激活一组催化基因组去甲基化的酶，可以解决增强子高甲基化问题，从而在体外重新启动关键骨髓基因的表达。这些发现表明，TET 和 IDH 突变积极促进了 AML 标志性的分化阻断，并且这种情况可以通过已知的无毒分子轻松逆转。在本提案中，我建议在临床前体内环境中单独探索维生素 C 的功效以及与其他去甲基化疗法联合使用的功效。此外，考虑到可以在疾病爆发之前使用常规诊断技术在个体中检测到 TET 和 IDH 突变，我建议探索高剂量维生素 C 补充剂恢复受影响细胞胞嘧啶甲基化稳态的潜力，最终目标是延迟或防止向骨髓恶性肿瘤的转化。