Pathogenetic roles of USO1 in leukemogenesis

USO1 在白血病发生中的致病作用

基本信息

批准号：
10359128
负责人：
Dinesh S Rao
金额：
$ 7.8万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359128
关键词：
Acute Lymphocytic Leukemia Antibodies Antibody Therapy B-Cell Acute Lymphoblastic Leukemia Binding Biochemical Biological Biological Assay Biological Models Bone Marrow Transplantation CD19 Antigens CRISPR screen CRISPR/Cas technology Cell Line Cell Survival Cell Therapy Cells Cellular biology Chemicals Child Chromosomal translocation Clinical Colon Carcinoma Data Development Diagnosis Exhibits Fusion Oncogene Proteins Future Genetic Models Genetic Transcription Goals Golgi Apparatus Grant Hematopoietic stem cells Immunoprecipitation Institutes Knock-out Leukemic Cell Link MLL-AF4 Malignant Childhood Neoplasm Malignant Neoplasms Membrane Molecular Biology Multiple Myeloma Mus Play Post-Transcriptional Regulation Prognosis Proteins RNA RNA Binding RNA Processing RNA-Binding Proteins Recommendation Reporting Research Research Project Grants Resistance Resources Role System Testing Therapeutic Time United States Vesicular Transport Proteins Work base cancer type chemotherapy clinical translation crosslink experimental study in vivo in vivo Model inhibitor leukemia leukemogenesis loss of function malignant breast neoplasm malignant stomach neoplasm novel novel diagnostics overexpression prognostic resistance mechanism retroviral transduction synergism targeted treatment trafficking transcriptome vesicle transport

项目摘要

PROJECT SUMMARY B-acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children. The protein USO1 is specifically overexpressed in B-acute lymphoblastic leukemia (B-ALL) with translocation t(4;11) MLL-AF4, which portends a dismal prognosis. This subtype of B-ALL, derived from a primitive hematopoietic progenitor cell, is particularly difficult to treat, even with the recently described, and generally successful, antibody- and cell-based therapies that target the CD19 antigen. USO1 is known to be upregulated in other cancer types, and regulates cell survival/proliferation in multiple cancer types. Studies of the cell biological role of USO1 have shown it be a of importance in vesicular trafficking, and recent high-throughput studies have shown that USO1 is an RNA binding protein in some cellular systems- suggesting that this protein may exhibit a novel function connecting post-transcriptional gene regulation to vesicular processing. In this proof-of-concept grant, we hypothesize that (1) USO1 plays a pathogenetic role in MLL-translocated leukemogenesis and that (2) USO1 is an RNA binding protein. In this grant, we will explore the roles of USO1 in cancer using loss-of-function genetic models in a novel in vivo system to study MLL-AF4-driven leukemia. Additionally, we will perform biochemical cross-linking and RNA immunoprecipitation assays to determine if USO1 binds to RNA in B-ALL cell lines. The three aims proposed are independent, self-contained, but also have significant synergy. Together, the successful completion of the aims will uncover whether USO1 plays a pathogenetic role in leukemia, and whether its function involves RNA-based mechanisms. These studies are uniquely suited to the R03 mechanism, which supports small research projects that can be carried out in a short time period with limited resources. However, these studies will also lay the groundwork for novel diagnostic, prognostic and therapeutic strategies in B-ALL.

项目摘要 B-急性淋巴细胞白血病（B-All）是儿童中最常见的恶性肿瘤。蛋白质USO1是特异性过表达的B-急性淋巴细胞白血病（B-all），易位t（4; 11）MLL-AF4，该白血病（4; 11）预后预后。 B-all的这种亚型，源自原始造血祖细胞，是即使最近描述且通常成功的抗体和基于细胞的抗体，也很难治疗靶向CD19抗原的疗法。已知USO1在其他癌症类型中被上调，并调节多种癌症类型的细胞存活/增殖。对USO1细胞生物学作用的研究表明它是在囊泡贩运中的重要性以及最近的高通量研究表明，USO1是RNA 在某些细胞系统中结合蛋白的结合蛋白 - 表明该蛋白可能表现出新的连接功能转录后基因调控囊泡加工。在这项概念证明的赠款中，我们假设（1）USO1在MLL转移的白血病发生中起致病作用，（2）USO1是RNA结合蛋白质。在这笔赠款中，我们将使用功能丧失遗传模型在A中探索USO1在癌症中的作用研究MLL-AF4驱动白血病的新型体内系统。此外，我们将执行生化交联和RNA免疫沉淀测定法，以确定USO1是否与B-all细胞系中的RNA结合。这三个目标拟议的是独立的，独立的，但也具有明显的协同作用。在一起，成功目的的完成将揭示USO1是否在白血病中起致病作用，以及它的功能是否扮演涉及基于RNA的机制。这些研究非常适合R03机制，该机制支持可以在很短的时间内以有限的资源进行的小型研究项目。但是，这些研究还将为B-all的新型诊断，预后和治疗策略提供基础。