Disordered epigenetic regulation of the CREBBP oncoprotein and of micro-RNA transcription in juvenile myelomonocytic leukemia at high risk of relapse

复发风险高的幼年型粒单核细胞白血病 CREBBP 癌蛋白和 micro-RNA 转录的表观遗传调控紊乱

• 批准号: 171803176
• 负责人: Professor Dr. Christian Flotho
• 金额: --
• 依托单位: Klinik für Pädiatrische Hämatologie und Onkologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/171803176?language=en
• 关键词: Disordered; epigenetic; regulation; CREBBP; oncoprotein

Our previous work indicates that juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm of early childhood, is a disease with impaired DNA methylation control. A subset of patients carry a leukemic clone with extensive DNA hypermethylation at specific target sites. These children face a serious risk of disease recurrence after transplantation. Using genome-wide CpG methylation profiling in a pilot series of JMML cases, we identified the cAMP-responsive element binding protein (CREB)-binding protein CREBBP, a transcriptional co-activator and histone acetyltransferase with a well-documented role in myeloid leukemogenesis, as a target of epigenetic modification in high-risk JMML. In addition, several loci encoding micro-RNAs were altered by DNA hypermethylation. Here we propose to investigate how epigenetic dysregulation 1) of CREBBP, and 2) of specific micro-RNAs, contributes functionally to the refractory JMML phenotype.First, we will perform a systematic screen for epigenetic CREBBP modification in an extended cohort of JMML patients, corroborate the adverse prognostic significance of such lesions, use reporter constructs to analyze the effects of CREBBP CpG island methylation on its expression in detail, study the expression patterns of CREBBP in low-risk versus high-risk JMML, look into the phenotypic consequences of experimental CREBBP repression in JMML, and define target promoters whose function is impaired when CREBBP becomes dysfunctional in JMML.Second, we will study the genome-wide spectrum of micro-RNAs with epigenetic promoter modification in JMML, identify target structures of aberrantly regulated micro-RNAs in JMML, and characterize the functional role of epigenetic micro-RNA silencing in this leukemia.We anticipate that these investigations will enhance our understanding of the close link between epigenetic aberrations and aggressive phenotype in JMML, that they will provide valuable insight into the role of epigenetic dysregulation in the initiation of myeloid leukemia, and that they will provide functional explanation for the high rate of failure after HSCT for JMML. Moreover, these studies will strengthen the preclinical rationale for the use of epigenetic therapy in JMML.

我们之前的工作表明，幼年粒单核细胞白血病（JMML）是一种儿童早期侵袭性骨髓增殖性肿瘤，是一种 DNA 甲基化控制受损的疾病。一部分患者携带在特定靶位点具有广泛 DNA 高甲基化的白血病克隆。这些儿童在移植后面临着疾病复发的严重风险。通过在一系列 JMML 病例中进行全基因组 CpG 甲基化分析，我们鉴定了 cAMP 响应元件结合蛋白 (CREB) 结合蛋白 CREBBP，这是一种转录共激活因子和组蛋白乙酰转移酶，在骨髓性白血病发生中具有明确的作用。作为高风险 JMML 中表观遗传修饰的目标。此外，DNA 高甲基化改变了几个编码 micro-RNA 的基因座。在此，我们建议研究 CREBBP 的表观遗传失调 1) 和特定 micro-RNA 的 2) 如何在功能上导致难治性 JMML 表型。首先，我们将在 JMML 患者的扩展队列中对表观遗传 CREBBP 修饰进行系统筛选，证实此类病变的不良预后意义，使用报告基因构建体详细分析 CREBBP CpG 岛甲基化对其表达的影响，研究低风险与高风险 JMML 中的 CREBBP，研究 JMML 中实验性 CREBBP 抑制的表型后果，并定义当 CREBBP 在 JMML 中功能失调时其功能受损的目标启动子。 -JMML 中具有表观遗传启动子修饰的 RNA，识别 JMML 中异常调控的 micro-RNA 的靶结构，并表征表观遗传 micro-RNA 的功能作用我们预计这些研究将增强我们对 JMML 中表观遗传畸变和侵袭性表型之间密切联系的理解，它们将为了解表观遗传失调在髓系白血病起始中的作用提供有价值的见解，并且它们将为 JMML HSCT 后的高失败率提供功能解释。此外，这些研究将加强在 JMML 中使用表观遗传疗法的临床前理论基础。