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-摘要： 急性髓系白血病 (AML) 常见的遗传异常之一是易位 染色体 8q22 和染色体 21q22 [t(8;21)(q22;q22)] 之间，产生 AML1-ETO (AE)融合基因。 AE 是一种转录因子，当其表达时，会阻止正常的骨髓分化并 对 t(8;21) 白血病发生至关重要，可导致未成熟白血病母细胞的增殖。然而， 单独的 t(8;21) 不足以促进白血病的发展，这需要额外的“打击”。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 转录水平要高得多 诊断时的 t(8;21)+ 白血病/造血干细胞与缓解时的 t(8;21)+ 白血病/造血干细胞，以及 t(8;21)+ 白血病母细胞与缓解时的 t(8;21)+ 白血病母细胞 t(8;21)+ 分化的单核细胞/粒细胞。这些数据表明，增加 AE 转录水平是 对于阻断分化和维持 t(8;21) 白血病都很重要。额外的初步数据 暗示转录后稳定性与 AE 3' 未翻译内的特定顺式元件相关 区域（UTR）是 AE 表达增加的主要贡献者。但尚不清楚还有哪些额外的 反式因子与 AE 3'UTR 顺式元件相互作用并增强白血病细胞中的 AE 表达。识别 白血病发生过程中转录后调控的分子机制可能提供有价值的信息 对治疗相关恶性肿瘤的合理治疗药物设计的见解。该提案旨在 确定控制AE增强表达的转录后机制及其 对 t(8;21) 白血病的发生和维持的贡献。 mRNA转录本的稳定性主要是 通过 3'UTR 与 microRNA (miRNA) 和 RNA 结合的序列特异性相互作用进行调节 蛋白质（RBP），这两种蛋白质在癌症中经常失调。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 的功能障碍导致 AE 增强 t(8;21) 白血病细胞中的表达。具体目标是识别针对 AE 的 miRNA 和 RBP 3’UTR 并确定它们对 AE 表达和 t(8;21) 白血病的贡献。