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

摘要-摘要： 急性髓细胞白血病（AML）中常见的遗传异常之一是易位， 在染色体8 q22和染色体21 q22 [t（8;21）（q22;q22）]之间，这引起AML 1-ETO (AE)融合基因AE是一种转录因子，当表达时，阻断正常的骨髓分化， 对t（8;21）白血病的发生至关重要，导致未成熟白血病母细胞的增殖。然而，在这方面， 单独的t（8;21）对于白血病的发展是不够的，这需要额外的“命中”。有趣的是，t（8;21） 来自我们和其他人的患者单细胞qPCR数据显示，AE转录物水平在 诊断时t（8;21）+白血病/造血干细胞与缓解时，以及t（8;21）+白血病原始细胞与 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， 对阻断分化和维持T（8;21）白血病都很重要。其他初步数据 暗示转录后稳定性，与AE 3'非翻译区内的特定顺式元件相关， 非翻译区（UTR）是增加AE表达的主要贡献者。然而，尚不清楚哪些额外的 反式因子与AE 3 'UTR顺式元件相互作用并增强AE在白血病细胞中的表达。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 对治疗相关恶性肿瘤的合理治疗药物设计的见解。这项建议旨在 确定控制AE表达增强的转录后机制， T（8;21）白血病的发生和维持。mRNA转录本的稳定性主要是 通过3 'UTR与microRNA（miRNAs）的序列特异性相互作用和RNA结合来调节 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miRNA和RBP的功能障碍有助于增强AE 在t（8;21）白血病细胞中的表达。具体目标是鉴定靶向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。

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.