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.

我们以前的工作表明，幼年性白血病（JMML）是一种幼年的侵袭性骨髓增生性肿瘤，是一种患有DNA甲基化控制受损的疾病。一部分患者携带白血病克隆，在特定靶位点上具有广泛的DNA高甲基化。这些孩子在移植后面临严重的疾病复发风险。在一系列JMML病例中，使用全基因组CPG甲基化分析，我们确定了cAMP响应元件结合蛋白（CREB）结合蛋白CREBBP，一种转录共激活剂和组蛋白乙酰转移酶，具有良好的骨髓性白血病生成中的作用，如髓样jmmentific of Especific of Especifific of Espementecific of Espemeneensenecentifectififif。另外，通过DNA高甲基化改变了几个编码微RNA的基因座。 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岛甲基化在其详细的表达上，研究CREBBP在低风险与高风险JMML中的表达模式，探讨JMML实验性CREBBP抑制的表型后果，定义目标促进者的功能在CREBBP在JMML.Second中的功能受损时，其功能会受到损害。表观遗传启动子在JMML中的修改，确定JMML中异常调节的微RNA的目标结构，并表征了该白血病中的遗传微RNA沉默的功能作用。我们预计，这些研究将增强我们对我们对jmml中有价值的启动的联系，使我们对jmml的近距离联系的理解增强，以实现启动，以实现启用jmml，以实现启发性，以实现启发性，以实现自己的启发性，以实现启发性，以实现启发性，以实现自己的启发性。髓样白血病的含量，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原理。