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

摘要-摘要： 易位是急性髓系白血病(AML)常见的遗传异常之一 在染色体8q22和21q22[t(8；21)(q22；q22)]之间，产生了AML1-ETO (AE)融合基因。AE是一种转录因子，当表达时，会阻止正常的髓系分化和 对t(8；21)白血病的发生起关键作用，导致未成熟白血病原始细胞的增殖。然而， 单靠T(8；21)是不足以发展成白血病的，这需要更多的“点击”。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，在 初诊和缓解期t(8；21)+白血病/造血干细胞和t(8；21)+白血病母细胞与缓解期 T(8；21)+分化的单核/粒细胞。这些数据表明，提高AE转录水平是 对阻断分化和维持t(8；21)白血病都很重要。其他初步数据 暗示转录后的稳定性，与AE3‘未翻译的特定顺式元件有关 区域(UTR)是AE表达增加的主要贡献者。然而，目前尚不清楚还增加了哪些 反式因子与AE3‘非编码区顺式元件相互作用，增强白血病细胞中AE3’UTR顺式元件的表达。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及其受体表达增强的转录后机制 T(8；21)白血病的发病和维持。Mrna转录本的稳定性主要是 通过3‘非编码区与microRNAs(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通常都是失调的。因此，拟议的研究旨在测试 假设某些AE3‘非编码区相互作用的miRNAs和RBPs功能障碍是增强AEs的原因 在t(8；21)白血病细胞中表达。具体目标是识别针对AE的miRNAs和RBP 3‘非编码区，确定它们在AE表达和t(8；21)白血病中的作用。

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.