Function of Musashi-2 Methylation in Normal and Malignant Hematopoiesis

项目摘要 急性髓性白血病（AML）是一种侵袭性、异质性疾病， 其特征在于未成熟髓系祖细胞的扩增和髓系祖细胞的抑制。 分化AML是在复杂的血液形成过程中发生的， 造血系统出了问题虽然在开发新的治疗方法和 在治疗AML方面，过去几十年来几乎没有取得进展。Musashi（MSI）家族 MSI 1和MSI 2是RNA结合蛋白（RBP），负责蛋白质的后 干细胞区室中基因的转录调控。然而，MSI 2发挥着主导作用， MSI 1在血液中的作用在这里，MSI 2维持造血干细胞（HSC）并决定 血统偏见。MSI 2与多种实体瘤和白血病有关，这表明MSI 2在肿瘤中的作用是重要的。 以它为靶点可能是一种有益的癌症治疗方法。先前的研究表明MSI 2表达 是AML和骨髓增生异常综合征（MDS）的阴性预后标志物， MSI 2与患者的不良预后和更差的临床结果相关。MSI 2合作 与融合蛋白BCR-ABL 1在白血病发生过程中，加强HSC转化， 其他突变的存在。MSI 2还能够维持混合谱系白血病（MLL）干细胞 通过与Hoxa 9、Myc和Ikzf 2 mRNA的相互作用来调控细胞程序。删除MSI 2 降低LSC存活并延迟体内白血病的发生和进展。许多研究 证明MSI 2在调节HSC中的翻译中具有多种责任， 白血病干细胞，但仍然有一个显着的知识差距，如何MSI 2的功能是 监管.拟议的项目目标将确定MSI 2功能在不同的后处理过程中如何变化。 添加翻译修饰。我们的初步数据表明精氨酸蛋白 甲基转移酶（PRMT）1和5可以甲基化MSI 2，并且在全基因组CRISPR筛选中， MSI 2是对PRMT 5抑制的抗性的最主要驱动因素。该提案将扩大我们的 了解MSI 2在正常和恶性干细胞调节程序中的功能， 设计治疗AML的新治疗策略。

Project Abstract Acute myeloid leukemia (AML) is an aggressive, heterogeneous disease and is characterized by the expansion of immature myeloid progenitors and the inhibition of myeloid differentiation. AML arises when the complex process of blood formation, known as hematopoiesis, goes wrong. While progress has been made to develop new treatments and therapies for AML, little progress has been made in the past decades. The Musashi (MSI) family of proteins, MSI1 and MSI2 are RNA-binding proteins (RBPs) and are responsible for post- transcriptional regulation of genes in stem cell compartments. However, MSI2 plays a prevailing role to MSI1 in the blood. Here, MSI2 maintains hematopoietic stem cells (HSCs) and determines lineage bias. MSI2 has been implicated in a variety of solid tumors and leukemias suggesting targeting it could be a beneficial cancer therapy. Previous studies demonstrate MSI2 expression is a negative prognostic marker for AML and myelodysplastic syndromes (MDS) as upregulation of MSI2 correlates with poor prognosis and worse clinical outcomes for patients. MSI2 cooperates with the fusion protein BCR-ABL1 during leukemogenesis, potentiating HSC transformation in the presence of other mutations. MSI2 is also able to sustain the mixed-lineage leukemia (MLL) stem cell regulatory program through interaction with Hoxa9, Myc, and Ikzf2 mRNAs. Deletion of MSI2 decreases LSC survival and delays leukemia initiation and progression in vivo. Many studies demonstrate the variety of responsibilities MSI2 has in regulating translation in HSCs and leukemic stem cells, but there remains a significant gap in knowledge as to how MSI2 function is regulated. The proposed project aims will define how MSI2 function changes when different post- translational modifications are added. Our preliminary data establishes protein arginine methyltransferases (PRMT) 1 and 5 can methylate MSI2, and in a genome wide CRISPR screen, MSI2 was the top driver of resistance to PRMT5 inhibition. The outlined proposal will expand our understanding of MSI2 function in normal and malignant stem cell regulatory programs to inform design of novel therapeutic strategies to treat AML.