Distinct acute myeloid leukemia subclasses with CEBPA mutations

描述(由申请人提供)：了解血细胞正常发育的潜在机制将导致对急性白血病发病机制的新理解。长期目标是加深我们对白血病相关机制的理解，开发基于分子机制的新的预后分类，然后通过实验验证这些靶基因和途径，以便最终开发出更特异、毒性更低的白血病和其他癌症的治疗方法。转录因子C/EBPα对正常髓系细胞的分化是绝对关键的，并且在特定的AML亚型中被干扰(突变或表达降低)。最近的研究表明，在C/EBPα突变患者中存在明显的基因表达簇，以及新的靶基因。在接下来的5年里，我们建议建立这些簇可以用于新的预后策略，以及更多地了解C/EBPα突变如何导致分化障碍的机制，以便根据分子机制知识开发特定治疗策略。因此，我们提出了以下具体目标：(1)鉴定其基因表达模式具有C/EBPα突变特征的人AML簇(“C/EBPα簇”)；(2)研究C/EBPα突变蛋白未能诱导粒细胞分化的机制；(3)检测C/EBPα突变蛋白在体内的功能。这些研究将导致新的预后工具，以及为未来的治疗干预识别新的靶向途径。这项研究与公共卫生的相关性：这项研究的目的是更好地了解与急性髓系白血病(AML)发展有关的基因，以便开发更好的诊断和预后工具以及新的治疗方法。在这项提案中，我们将描述一种特殊类型的AML，这种AML的特征是一种名为C/EBPα的基因异常，该基因在非白血病细胞中指导分化过程。我们将开发诊断工具来识别这些患者，并研究异常C/EBPα基因产物未能指导分化导致白血病发生的机制。

DESCRIPTION (provided by applicant): Knowledge of the mechanisms underlying the normal development of blood cells will lead to new understanding of the pathogenesis of acute leukemias. The long range goals are to further our understanding of the mechanisms involved in leukemia, to develop new prognostic classifications based on molecular mechanisms, and then to experimentally validate these target genes and pathways in order to eventually develop more specific, less toxic therapies for leukemia and other cancers. The transcription factor C/EBP alpha is absolutely critical for differentiation of normal myeloid blasts, and disrupted (mutations or decreased expression) in specific subtypes of AML. Recent studies have demonstrated distinct gene expression clusters in patients with mutations in C/EBP alpha, as well as new target genes. Over the next 5 years, we propose to establish that these clusters can be utilized for new prognostic strategies, as well as to understand more about the mechanism of how mutations of C/EBP alpha lead to a block in differentiation in order to develop strategies for specific treatments based on knowledge of the molecular mechanisms. We therefore propose the following Specific Aims: (1) To characterize human AML clusters whose gene expression pattern is characteristic of C/EBP alpha mutations ("C/EBP alpha clusters"); (2) To study the mechanisms by which C/EBP alpha mutant proteins fail to induce granulocytic differentiation; and (3) To test the function of C/EBP alpha mutant protein in vivo. These studies will lead to novel prognostic tools, as well as the identification of novel target pathways for therapeutic intervention in the future. Relevance of this research to public health: The aim of this research is to better understand the genes involved in the development of acute myeloid leukemia (AML) in order to develop better diagnostic and prognostic tools as well as new therapies. In this proposal, we will characterize a specific type of AML, one that is characterized by abnormalities in a gene called C/EBP alpha, which in non-leukemic cells directs the differentiation process. We will develop diagnostic tools to identify these patients, as well as study the mechanisms of how the failure of the abnormal C/EBP alpha gene product to direct differentiation leads to the development of leukemia.