AML1-ETO Regulation via the 3'UTR in t(8;21) Acute Myeloid Leukemia

t(8;21) 急性髓系白血病中 AML1-ETO 通过 3UTR 的调节

• 批准号: 9925747
• 负责人: Daniel Thomas Johnson
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-02 至 2021-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925747
• 关键词: 3' Untranslated Regions; AML1-ETO fusion protein; Acute Myelocytic Leukemia; Address; Affinity Chromatography; Area; Binding Proteins; Biogenesis; Biological Assay; Biotin; Blast Cell; Cell Line; Cell Proliferation; Cells; Chromosomes; Data; Data Set; Development; Diagnosis; Disease remission; Drug Design; Elements; Fellowship; Functional disorder; Genetic Transcription; Half-Life; Hematopoietic; Hematopoietic stem cells; Immunoprecipitation; Investigation; Knowledge; Lead; Length; Leukemic Cell; Luciferases; Maintenance; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Methods; MicroRNAs; Molecular; Molecular Abnormality; Myelogenous; Oncogenes; Patients; Phenotype; Post-Transcriptional Regulation; Proteins; RNA; RNA-Binding Proteins; Regulation; Relapse; Reporter; Role; Sampling; Testing; Therapeutic; Transcript; Viral; Work; acute myeloid leukemia cell; base; cancer type; effective therapy; fusion gene; granulocyte; in vivo; insight; knock-down; leukemia; leukemogenesis; mRNA Stability; monocyte; novel; novel therapeutic intervention; overexpression; t(8; 21)(q22; q22); transcription factor; tumorigenesis; tumorigenic

Summary-Abstract: One of the common genetic abnormalities in acute myeloid leukemia (AML) is the translocation between chromosome 8q22 and chromosome 21q22 [t(8;21)(q22;q22)], which gives rise to the AML1-ETO (AE) fusion gene. AE is a transcription factor that, when expressed, blocks normal myeloid differentiation and is critical to t(8;21) leukemogenesis, leading to the proliferation of immature leukemic blast cells. However, t(8;21) alone is insufficient for leukemia development, which requires additional “hits.” Interestingly, t(8;21) patient single-cell qPCR data from ourselves and others shows that the AE transcript level is much greater in both t(8;21)+ leukemic/hematopoietic stem cells at diagnosis vs remission, and in t(8;21)+ leukemic blasts vs t(8;21)+ differentiated monocytes/granulocytes. These data suggest that increasing AE transcript levels is important to both blocking differentiation and maintaining t(8;21) leukemia. Additional preliminary data implicates that post-transcriptional stability, associated with specific cis-elements within the AE 3’ untranslated region (UTR), is a major contributor to increased AE expression. However, it is unknown which additional trans-factors interact with the AE 3’UTR cis-elements and enhance AE expression in leukemic cells. Identifying the molecular mechanisms of post-transcriptional regulation during leukemogenesis may provide valuable insights into the rational therapeutic drug design for treating related malignancies. This proposal seeks to determine the post-transcriptional mechanisms controlling the enhanced expression of AE and their contribution to the initiation and maintenance of t(8;21) leukemia. The stability of mRNA transcripts is primarily regulated through sequence specific interactions of the 3’UTR with microRNAs (miRNAs) and RNA binding proteins (RBPs), which are both often dysregulated in cancer. Therefore, the proposed studies aim to test the hypothesis that dysfunction of certain AE 3’UTR-interacting miRNAs and RBPs contributes to the enhanced AE expression in t(8;21) leukemic cells. The specific aims are to identify miRNAs and RBPs that target the AE 3’UTR and determine their contribution to AE expression and t(8;21) leukemia.

摘要抽取： 急性髓样白血病（AML）中常见的遗传异常之一是易位 在8Q22染色体和21q22染色体之间 （AE）融合基因。 AE是一种转录因子，当表达时，它会阻止正常的髓样分化和 对于t（8; 21）白血病至关重要，导致未成熟的白血病爆炸细胞的增殖。然而， 单独使用t（8; 21）对于白血病的发展不足，这需要额外的“命中”。有趣的是，T（8; 21） 来自我们自己和其他人的患者单细胞QPCR数据表明，AE转录级别更大 T（8; 21）+诊断时的白血病/造血干细胞与缓解相比，在T（8; 21）+白血病爆炸中 t（8; 21）+分化的单核细胞/粒细胞。这些数据表明，提高AE的转录水平是 对于阻止分化和维持t（8; 21）白血病很重要。其他初步数据 暗示转录后稳定性与AE 3'未翻译中的特定顺式元素相关 区域（UTR）是增加AE表达的主要贡献者。但是，尚不清楚哪个附加 跨因素与AE 3'UTR顺元相互作用，并增强白血病细胞中的AE表达。识别 在白血病发生过程中转录后调节的分子机制可能会提供有价值的 对治疗相关恶性肿瘤的理性治疗药物设计的见解。该提议试图 确定控制AE及其增强表达的转录后机制 对T（8; 21）白血病的主动性和维持的贡献。 mRNA转录本的稳定性是主要的 通过3'UTR与microRNA（miRNA）和RNA结合的序列特异性相互作用调节 蛋白质（RBP），它们在癌症中经常失调。因此，拟议的研究旨在测试 假设某些AE 3'UTR相互作用的miRNA和RBP的功能障碍有助于增强AE T（8; 21）白血病细胞中的表达。具体目的是识别针对AE的miRNA和RBP 3’UTR并确定它们对AE表达的贡献和T（8; 21）白血病。