Deregulated microRNAs in Acute Myeloid Leukemia

急性髓系白血病中 microRNA 失调

• 批准号: 8739619
• 负责人: Sayyed Kaleem Zaidi
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-23 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8739619
• 关键词: 3' Untranslated Regions; AML1-ETO fusion protein; Acute Myelocytic Leukemia; Algorithms; Apoptosis; Apoptotic; Binding Sites; Biochemical; Bioinformatics; Biological; Biological Assay; Catalytic RNA; Cell Line; Cell Proliferation; Cells; Cellular biology; Chemicals; Chimeric Proteins; Chromosomal translocation; Chromosomes, Human, Pair 8; Cleaved cell; Computer Simulation; DNA Binding; Diagnostic; Differentiation and Growth; Dimensions; Etiology; Figs - dietary; Functional RNA; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Growth Factor; Health; Hematopoiesis; Hematopoietic; Human; Investigation; Leukemic Cell; Link; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Myelogenous; Myeloid Cells; Myeloid Leukemia; Nuclear Matrix; Oncogenic; Online Systems; Outcome; Pathology; Pathway Analysis; Pathway interactions; Patients; Probability; Promoter Regions; Property; Protein Binding; Proteins; RNA; RNA Interference; RUNX1 gene; Recruitment Activity; Reporter; Role; Sampling; Signal Transduction; Specificity; Testing; Therapeutic; Transcript; Transcriptional Activation; acute myeloid leukemia 1 protein; base; chromatin immunoprecipitation; chromatin remodeling; clinically relevant; cohort; genetic regulatory protein; genome-wide; human CBFA2T1 protein; inhibitor/antagonist; leukemia; leukemogenesis; novel; programs; promoter; public health relevance; response; t(8; 21)(q22; q22); transcription factor

DESCRIPTION (provided by applicant): One in four patients with acute myeloid leukemia (AML), a major hematopoietic abnormality in the US, carry the 8;21 chromosomal translocation [t(8;21)]. This translocation disrupts the gene for a key hematopoietic Runx1/AML1 transcription factor and encodes the leukemic AML1-ETO protein. AML1-ETO modifies transcription program of myeloid cells by altering Runx1 subnuclear localization and deregulating Runx target genes. Not only does Runx1 control the expression of hematopoiesis-related genes, it may also transcriptionally regulate miRs, which have recently been implicated in human leukemias. However, this hypothesis has not been experimentally tested. Furthermore, role of miRs in myeloid cell biology and their deregulation in acute myeloid leukemias by chimeric proteins such as AML1-ETO remains under explored. Our central hypothesis is that miRs that are direct transcriptional targets of Runx1 in myeloid lineage are key regulators of hematopoiesis and leukemogenesis. This hypothesis will be tested by an integrated experimental approach. Through genome-wide miR profiling of AML patients carrying the t(8;21), we will identify and characterize miRs that are deregulated in leukemia (henceforth designated Deregulated in Leukemia-microRNAs or DiL-miRs; Specific Aim 1.1). By employing an integrated bioinformatics, cell biological and biochemical approach, we will focus on DiL-miRs that are direct transcriptional targets of either the wild type Runx1 or the leukemic AML1-ETO, potentially target key pathways or regulators in myeloid cells, and contribute to leukemogenic properties of AML1-ETO (Specific Aim 1.2). We anticipate that the study proposed in this Specific Aim will yield a focused subset of DiL-miRs with potential diagnostic value. The rationale for Specific Aim 2 is provided by the observation that the 3'UTR region of the translocated AML1- ETO gene transcript is contributed by the ETO gene and is distinct from that of the wild type Runx1 gene transcript. We will specifically focus on miRs that are predicted to target the 3'UTR of AML1-ETO but not that of Runx1 gene transcript. These miRs will be assessed for their potential to partially or fully reverse the leukemic properties of AML1-ETO in patient-derived leukemia cell lines. We anticipate that the outcome of this Specific Aim will yield a subset of miRs that specifically and selectively target AML1-ETO and are therapeutically relevant. We propose that understanding mechanisms through which DiL-miRs participate in myeloid cell biology as well as in pathology of AML will provide a novel dimension to developing specific and effective therapeutic approaches for treatment of leukemia.

描述（由申请人提供）：四分之一的患有急性髓样白血病（AML）的患者是美国的主要造血异常，携带8; 21染色体易位[T（8; 21）]。这种转运破坏了关键造血Runx1/AML1转录因子的基因，并编码白血病AML1-Eto蛋白。 AML1-Eto通过改变Runx1亚核定位并放弃RUNX靶基因来修饰髓样细胞的转录程序。 Runx1不仅控制造血相关基因的表达，而且还可以在转录上调节MIR，这最近与人类白血病有关。但是，该假设尚未进行实验检验。此外，MIR在髓样细胞生物学中的作用及其在嵌合蛋白（如AML1-Eto）中的急性髓样白血病中的失调仍在探索。我们的中心假设是，髓样谱系中Runx1的直接转录靶标的miR是造血和白血病发生的关键调节剂。该假设将通过综合实验方法进行检验。通过携带T（8; 21）的AML患者的全基因组MIR分析，我们将识别和表征在白血病中失控的MIR（此后指定在白血病 - 米尔纳斯或DIL-MIRS中指定失控的miR；特定的目标1.1）。通过采用综合生物信息学，细胞生物学和生物化学方法，我们将专注于DIL-MIRS，是野生型Runx1或白血病AML1-Eto的直接转录靶标的DIL-MIR，潜在的靶向靶向关键途径或髓样细胞的调节剂，并为AML1-Eto的白血病特性做出贡献。我们预计，在此特定目标中提出的研究将产生具有潜在诊断价值的DIL-MIR的集中子集。特定目标2的基本原理是通过观察到的，即易位的AML1- ETO基因转录本的3'UTR区域由ETO基因贡献，并且与野生型Runx1基因转录本的贡献不同。我们将特别关注预测的MIR，以瞄准AML1-Eto的3'UTR，但不是Runx1基因转录本的miR。这些miR将因其在患者衍生的白血病细胞系中部分或完全逆转AML1-Eto的白血病特性而进行评估。我们预计这个特定目标的结果将产生 特别有选择地靶向AML1-Eto并在治疗上相关的MIR子集。我们建议理解DIL-MIR参与髓样细胞生物学以及AML病理学的机制，将为开发特定有效的治疗方法来治疗白血病。