Characterizing the MSI2 network in leukemia

白血病中 MSI2 网络的特征

• 批准号: 10157187
• 负责人: Michael Kharas
• 金额: $ 41.32万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10157187
• 关键词: 3' Untranslated Regions; Acute Myelocytic Leukemia; Address; Advanced Malignant Neoplasm; Arginine; Binding; Binding Proteins; Binding Sites; Blood; Blood Cells; CD34 gene; CRISPR screen; Cells; Clinical; Communication; Cytotoxic agent; Data; Dependence; Development; Disease; Enzymes; Epigenetic Process; Equilibrium; Exhibits; Family; Family Study; Family member; Frequencies; Genetic Models; Hematologic Neoplasms; Hematopoietic stem cells; Human; Knockout Mice; Laboratories; Leukemic Cell; Link; Lymphoma cell; Malignant Neoplasms; Mammalian Cell; Maps; Measures; Mediating; Medicine; Messenger RNA; Methylation; Modification; Molecular; Mus; Mutation; Myeloid Leukemia; Nature; Normal Cell; Outcome; Pathogenesis; Pathway interactions; Patients; Post-Translational Protein Processing; Prognostic Marker; Proteins; RNA Binding; RNA Editing; RNA Recognition Motif; RNA Splicing; RNA-Binding Proteins; Reagent; Regulation; Relapse; Resistance; Role; Sampling; Site; Solid Neoplasm; Stem Cell Development; System; Therapeutic; Time; Transferase; Translations; base; cancer therapy; cell growth; chemotherapy; epigenome; genome-wide; inhibitor/antagonist; leukemia; leukemia/lymphoma; leukemic stem cell; leukemogenesis; molecular targeted therapies; mouse model; myeloid leukemia cell; novel; novel strategies; novel therapeutic intervention; programs; protein function; response; stem cell biology; stem cell function; stem cells; therapeutic target; transcriptome sequencing

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.

项目摘要/摘要 进化保守的发育计划在造血干细胞（HSC）中仔细维持。 遗传改变和表观遗传机制可以改变正常血液发育的平衡，从而导致 血液学恶性肿瘤。我们的实验室和其他人发现Musashi2（MSI2）RNA结合 蛋白质在最具侵略性的癌症中高度表达，并预测急性的临床结果不佳 髓样白血病（AML）患者。遗传模型发现白血病干细胞需要MSI2 功能。利用一种新方法来识别RNA结合蛋白的mRNA靶标，我们发现MSI2 与正常的干细胞和祖细胞相比，白血病干细胞中的活性增加。这令人惊讶 发现表明RNA结合蛋白功能可能不仅仅是表达差异的失调。 我们假设RNA结合蛋白的MSI家族在AML中具有差异 正常细胞和MSI增强了AML中失调的表观遗传组。我们建议两个 这个有趣的发现的机制1）MSI2相关的RBP竞争MSI2结合位点，2） 翻译修改可以调节MSI2活性。我们的初步数据发现MSI2可以 介导对PRMT5的耐药性，PRMT1和PRMT5可以直接甲基化MSI2。 PRMT5抑制剂是 作为治疗靶标进行了调查，我们的建议提出了与这一途径的新链接，可以 解释细胞上下文MSI2活性。我们的建议将利用新的遗传模型来表征MSI2目标 特定的蜂窝环境并探索MSI2相关程序，以确定新的治疗策略 AML。