Characterizing the MSI2 network in leukemia

项目总结/摘要 在造血干细胞（HSC）中小心地维持进化保守的发育程序。 遗传改变和表观遗传机制可以改变正常血液发育的平衡， 血液恶性肿瘤我们的实验室和其他人已经发现，MUSASHI 2（MSI 2）RNA结合 蛋白质在最具侵袭性的癌症中高度表达，并且在急性肿瘤中预测不良的临床结果。 骨髓性白血病（AML）患者。遗传模型发现MSI 2是白血病干细胞所必需的。 功能利用一种新的方法来鉴定RNA结合蛋白的mRNA靶点，我们发现MSI 2 与正常干细胞和祖细胞相比，白血病干细胞中的活性增加。这种令人惊讶 这一发现表明，RNA结合蛋白的功能失调可能不仅仅是表达差异。 我们推测，MSI家族的RNA结合蛋白在AML中的活性与 MSI增强AML中失调的表观基因组。我们提出两种可能的 这一有趣发现的机制1）MSI 2相关的RBP竞争MSI 2结合位点和2）后- 翻译修饰可以调节MSI 2活性。我们的初步数据显示MSI 2可以 介导对PRMT 5的抗性，并且PRMT 1和PRMT 5可以直接甲基化MSI 2。PRMT 5抑制剂是 作为治疗靶点进行研究，我们的建议表明了与该途径的新联系， 解释细胞环境MSI 2活性。我们的提案将利用新的遗传模型来表征MSI 2靶点， 特定的细胞环境，并探索MSI 2相关的程序，以确定新的治疗策略， 急性髓细胞白血病

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.