Characterizing the MSI2 network in leukemia

项目摘要/摘要 在造血干细胞(HSCs)中小心地维持着一个进化保守的发育程序。 基因改变和表观遗传机制可以改变正常血液发育的平衡，导致 恶性血液病。我们的实验室和其他人已经发现MUSASHI2(MSI2)RNA结合 蛋白质在最具侵袭性的癌症中高度表达，并预测急性白血病的临床预后较差 髓系白血病(AML)患者。遗传模型发现白血病干细胞需要MSI2 功能。利用一种新的方法鉴定RNA结合蛋白的mRNA靶标，我们发现MSI2 与正常干细胞和祖细胞相比，白血病干细胞的活性增强。令人惊讶的是 研究结果表明，RNA结合蛋白的功能可能会受到失调，而不仅仅是表达差异。 我们假设MSI家族的RNA结合蛋白在AML中具有不同的活性。 该MSI增强了AML中异常调节的表观基因组。我们提出了两种可能性 这一耐人寻味的发现的机制1)与MSI2相关的限制性商业惯例竞争MSI2结合位点，2)POST- 翻译修饰可以调节MSI2的活动。我们的初步数据发现，MSI2可以 介导对PRMT5的抗性，并且PRMT1和PRMT5可以直接甲基化MSI2。PRMT5抑制剂是 正在作为治疗靶点进行研究，我们的建议表明了与这一途径的新联系，并可能 解释单元格上下文MSI2活动。我们的建议将利用新的遗传模型来表征MSI2靶标 并探索MSI2相关计划，以确定新的治疗策略 AML。

PROJECT SUMMARY/ABSTRACT An evolutionary conserved developmental program is carefully maintained in hematopoietic stem cells (HSCs). Genetic alterations and epigenetic mechanisms can alter the balance of normal blood development resulting in hematological malignancies. Our laboratory and others have found that the MUSASHI2 (MSI2) RNA binding proteins is highly expressed in the most aggressive cancers and predicts a poor clinical outcome in acute myeloid leukemia (AML) patients. Genetic models have found that MSI2 is required for leukemia stem cell function. Utilizing a new way to identify mRNA targets of RNA binding proteins, we have found that MSI2 activity is increased in leukemia stem cells compared to normal stem and progenitor cells. This surprising finding suggests that RNA binding protein function can be dysregulated beyond just expression differences. We hypothesize that the MSI family of RNA binding protein have differential activity in AML compared to normal cells and that MSI enhances the dysregulated epigenome in AML. We propose two possible mechanisms for this intriguing finding 1) MSI2 associated RBPs compete for MSI2-binding sites and 2) Post- translation modifications can modulate MSI2 activity. Our preliminary data has uncovered that MSI2 can mediate resistance to PRMT5 and that PRMT1 and PRMT5 can directly methylate MSI2. PRMT5 inhibitors are being investigated as therapeutic targets and our proposal suggests a novel link to this pathway and may explain cell context MSI2 activity. Our proposal will utilize new genetic models to characterize MSI2 targets in specific cellular contexts and explore the MSI2 associated program to identify new therapeutic strategies in AML.