Characterizing the MSI2 network in leukemia

白血病中 MSI2 网络的特征

基本信息

批准号：
10318669
负责人：
Michael Kharas
金额：
$ 40.5万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
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/10318669
关键词：
3&apos 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 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

3&apos 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 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

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项目摘要

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 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 血液学恶性肿瘤。 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 功能。 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 这个有趣的发现的机制1）MSI2相关的RBP竞争MSI2结合位点，2） 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.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。