Function of Musashi-2 Methylation in Normal and Malignant Hematopoiesis

Musashi-2 甲基化在正常和恶性造血中的功能

• 批准号: 10643947
• 负责人: Chiara Evans
• 金额: $ 4.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10643947
• 关键词: ABL1 gene; Acute Myelocytic Leukemia; Advanced Malignant Neoplasm; Affect; Arginine; Blood; C-terminal; CRISPR screen; Cell Compartmentation; Cell Line; Cell Maintenance; Cells; Chimeric Proteins; Clinical; Co-Immunoprecipitations; Complex; Data; Development; Disease; Dysmyelopoietic Syndromes; Exons; Hematopoiesis; Hematopoietic stem cells; Knowledge; Laboratories; Lymphoma; MLLT3 gene; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Memorial Sloan-Kettering Cancer Center; Messenger RNA; Methylation; Mixed-Lineage Leukemia; Modification; Mus; Mutation; Myelogenous; Myeloid Leukemia; Oncogenic; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphorylation; Play; Post-Transcriptional Regulation; Post-Translational Protein Processing; Post-Translational Regulation; Process; Prognosis; Prognostic Marker; Protein Family; Protein-Arginine N-Methyltransferase; Proteins; RNA-Binding Proteins; Regulation; Research; Resistance; Role; Solid Neoplasm; System; Testing; Therapeutic; Tissues; Transfusion; Translational Activation; Translational Repression; Translations; Up-Regulation; Work; Writing; Xenopus oocyte; acute myeloid leukemia cell; bcr-abl Fusion Proteins; blood formation; cancer stem cell; cancer therapy; cell transformation; clinical prognosis; design; druggable target; genome-wide; in vivo; inhibitor; insight; leukemia; leukemic stem cell; leukemogenesis; mutant; mutant mouse model; novel; novel therapeutic intervention; oocyte maturation; progenitor; programs; recruit; response; stem cell survival; stem cells; whole genome

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.

项目摘要 急性髓样白血病（AML）是一种侵略性，异质性疾病，是 以未成熟髓样祖细胞的扩张和髓样的抑制为特征 分化。当复杂的血液形成过程（称为称为） 造血，出错。尽管已经取得了开发新疗法的进展，并且 AML的疗法，过去几十年来几乎没有取得进展。 Musashi（MSI）家庭 蛋白质，MSI1和MSI2是RNA结合蛋白（RBP），并负责 干细胞室中基因的转录调节。但是，MSI2播放 MSI1在血液中的作用。在这里，MSI2维持造血干细胞（HSC）并确定 血统偏见。 MSI2与多种实体瘤和白血病有关 靶向可能是一种有益的癌症治疗。先前的研究表明MSI2表达 是AML和骨髓增生综合征（MDS）的负预后标记 MSI2的预后不良和患者的临床结局较差。 MSI2合作 与融合蛋白BCR-ABL1在白血病发生过程中，增强了HSC转化 存在其他突变。 MSI2还能够维持混合乳清白血病（MLL）茎 通过与HOXA9，MYC和IKZF2 mRNA的相互作用来调节细胞调节程序。 MSI2的删除 降低LSC的存活率，并在体内延迟白血病的启动和进展。许多研究 证明MSI2在调节HSC中的翻译和 白血病干细胞，但关于MSI2函数的知识仍然存在很大的差距 受监管。提出的项目目标将定义MSI2函数在不同的后 - 添加了翻译修改。我们的初步数据建立了蛋白质精氨酸 甲基转移酶（PRMT）1和5可以甲基化MSI2，在基因组宽CRISPR筛选中， MSI2是对PRMT5抑制的最大驱动力。概述的提案将扩大我们的 了解正常和恶性干细胞调节程序中MSI2功能以告知 新型治疗AML的新型治疗策略的设计。