Function of Musashi-2 Methylation in Normal and Malignant Hematopoiesis

项目摘要 急性髓系白血病(AML)是一种侵袭性、异质性疾病， 以未成熟的髓系祖细胞扩增和髓系抑制为特征的 差异化。当复杂的血液形成过程，即所谓的 造血，出了问题。虽然在开发新的治疗方法和 对于急性髓细胞白血病的治疗，在过去的几十年里进展甚微。武藏(MSI)家族 在蛋白质中，MSI1和MSI2是RNA结合蛋白(RBP)，负责后处理。 干细胞室基因的转录调控。然而，MSI2扮演着一种流行的 在血液中扮演MSI1的角色。在这里，MSI2维持造血干细胞(HSCs)并决定 世系偏见。MSI2与多种实体肿瘤和白血病有关，提示 靶向它可能是一种有益的癌症治疗方法。先前的研究表明MSI2表达 是急性髓系白血病和骨髓增生异常综合征(MDS)上调的阴性预后标志 MSI2的表达与患者预后差、临床结局差相关。MSI2合作 与BCR-ABL1融合蛋白在白血病发生过程中，促进HSC转化 存在其他突变。MSI2也能够维持混合血统白血病(MLL)干细胞 通过与Hoxa9、Myc和Ikzf2 mRNAs的相互作用进行细胞调控。删除MSI2 降低LSC的存活率，延缓体内白血病的发生和发展。许多研究 演示MSI2在规范HSC中的翻译方面的各种职责以及 白血病干细胞，但关于MSI2是如何发挥作用的知识仍有很大差距 受监管的。拟议的项目目标将定义MSI2功能在不同的职位- 添加了翻译修改。我们的初步数据证实了蛋白质精氨酸 甲基转移酶(PRMT)1和5可以甲基化MSI2，在全基因组CRISPR筛查中， MSI2是PRMT5抑制抗性的最高驱动因子。概述的提案将扩大我们的 了解MSI2功能在正常和恶性干细胞调节程序中的作用 设计治疗急性髓系白血病的新治疗策略。

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.