Characterizing MSI2 in leukemia

白血病中 MSI2 的特征

基本信息

批准号：
9240611
负责人：
Michael Kharas
金额：
$ 41.48万
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 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240611
关键词：
Acute Myelocytic Leukemia Address Advanced Malignant Neoplasm Binding Binding Proteins Biological Assay Blood CD34 gene Cell Compartmentation Cell Line Cell physiology Cells Characteristics Clinical Cytotoxic agent Development Disease Epigenetic Process Equilibrium Family Family member Genetic Models Genetic Transcription Hematologic Neoplasms Hematological Disease Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Human Immunodeficient Mouse Journals Knock-out MLL-AF9 Malignant Neoplasms Medicine Memorial Sloan-Kettering Cancer Center Messenger RNA Modality Molecular Molecular Target Mus Mutation Myelogenous Myeloid Leukemia Nature Oncogenes Oncogenic Outcome Pathogenesis Pathway interactions Patients Population Prognostic Marker Proteins Publishing RNA RNA Recognition Motif RNA Stability RNA-Binding Proteins Reagent Regulation Relapse Reporting Resistance Role Sampling Solid Neoplasm Stem cells Therapeutic Translations Umbilical Cord Blood Untranslated Regions Xenograft procedure base bcr-abl Fusion Proteins cancer therapy chemotherapy epigenome genetic approach granulocyte improved inhibitor/antagonist insight kinase inhibitor leukemia leukemic stem cell loss of function macrophage molecular targeted therapies mouse model mutational status next generation novel novel strategies novel therapeutics outcome forecast overexpression patient stratification progenitor programs public health relevance response self-renewal stem cell biology targeted treatment therapeutic target therapy outcome treatment response

Acute Myelocytic Leukemia Address Advanced Malignant Neoplasm Binding Binding Proteins Biological Assay Blood CD34 gene Cell Compartmentation Cell Line Cell physiology Cells Characteristics Clinical Cytotoxic agent Development Disease Epigenetic Process Equilibrium Family Family member Genetic Models Genetic Transcription Hematologic Neoplasms Hematological Disease Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Human Immunodeficient Mouse Journals Knock-out MLL-AF9 Malignant Neoplasms Medicine Memorial Sloan-Kettering Cancer Center Messenger RNA Modality Molecular Molecular Target Mus Mutation Myelogenous Myeloid Leukemia Nature Oncogenes Oncogenic Outcome Pathogenesis Pathway interactions Patients Population Prognostic Marker Proteins Publishing RNA RNA Recognition Motif RNA Stability RNA-Binding Proteins Reagent Regulation Relapse Reporting Resistance Role Sampling Solid Neoplasm Stem cells Therapeutic Translations Umbilical Cord Blood Untranslated Regions Xenograft procedure base bcr-abl Fusion Proteins cancer therapy chemotherapy epigenome genetic approach granulocyte improved inhibitor/antagonist insight kinase inhibitor leukemia leukemic stem cell loss of function macrophage molecular targeted therapies mouse model mutational status next generation novel novel strategies novel therapeutics outcome forecast overexpression patient stratification progenitor programs public health relevance response self-renewal stem cell biology targeted treatment therapeutic target therapy outcome treatment response

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项目摘要

DESCRIPTION (provided by applicant): 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 recent studies have identified MUSASHI (MSI2), as an RNA binding protein that controls normal and leukemia self-renewal. Moreover, the MSI family is highly expressed in the most aggressive solid tumors and we have demonstrated that MSI2 expression predicts a worse clinical prognosis in acute myeloid leukemia (AML). We hypothesize that the RNA binding proteins MSI2 controls leukemic stem cell self-renewal and elucidating the mechanism of action for MSI2 in LSCs may provide novel therapeutic strategies in myeloid leukemia. This proposal utilizes Msi2 conditional knockouts and patient samples with AML to dissect the requirement for MSI2 in leukemia self-renewal. Furthermore, our global genetic approaches have already uncovered how regulation of translation alters several epigenetic pathways that are controlled by the MLL-AF9 oncogene. Our studies will examine the direct mRNA targets of MSI2 that control LSC function. Additionally, we will stratify patients based on their MSI2 expression and determine how cytotoxic agents, molecular targeted and epigenetic therapies can be used to improve therapeutic outcomes in AML.

描述（由适用提供）：在造血干细胞（HSC）中仔细维持了进化配置的发展程序。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。我们最近的研究确定了Musashi（MSI2），是控制正常和白血病自我更新的RNA结合蛋白。此外，MSI家族在最具侵略性的实体瘤中高度表达，我们已经证明MSI2表达预测急性髓细胞性白血病（AML）的临床预后较差。我们假设RNA结合蛋白MSI2控制白血病细胞自我更新并阐明LSC中MSI2的作用机理，可能会在髓样白血病中提供新颖的治疗策略。该提案利用MSI2有条件的敲除和AML的患者样品来剖定白血病自我更新中MSI2的需求。此外，我们的全球遗传方法已经发现了翻译的调节如何改变由MLL-AF9癌基因控制的几种表观遗传途径。我们的研究将检查控制LSC功能的MSI2的直接mRNA靶标。此外，我们将根据患者的MSI2表达对患者进行分层，并确定如何使用细胞毒性剂，分子靶向和表观遗传疗法来改善AML的治疗结果。