Pathogenetic roles of USO1 in leukemogenesis

项目总结 B-急性淋巴细胞白血病(B-ALL)是儿童最常见的恶性肿瘤。蛋白质USO1是 在易位为t(4；11)MLL-AF4的B-急性淋巴细胞白血病(B-ALL)中特异性高表达 预示着一个悲观的预后。这种亚型的B-ALL源于原始的造血祖细胞，是 特别难治疗，即使是最近描述的，通常是成功的基于抗体和细胞的 针对CD19抗原的治疗。已知USO1在其他癌症类型中上调，并调节 多种癌症类型中的细胞存活/增殖。对USO1细胞生物学作用的研究表明，它是一种 在囊泡运输中具有重要意义，最近的高通量研究表明USO1是一种RNA 某些细胞系统中的结合蛋白--表明该蛋白可能显示出一种连接 转录后基因调控对囊泡加工的影响。在这项概念验证拨款中，我们假设 (1)USO1在MLL易位白血病的发生中起致病作用；(2)USO1是一种RNA结合 蛋白。在这项资助中，我们将使用功能丧失遗传模型来探索USO1在癌症中的作用。 研究MLL-AF4驱动的白血病的新型体内系统。此外，我们还将进行生化交联剂 RNA免疫沉淀试验确定B-ALL细胞系中USO1是否与RNA结合。三个目标 建议都是独立的、自给自足的，但也具有显著的协同效应。团结在一起，成功的 这些目标的完成将揭示USO1是否在白血病中起致病作用，以及它的功能是否 涉及基于RNA的机制。这些研究特别适合R03机制，它支持 可以在短时间内用有限的资源进行的小型研究项目。然而，这些 研究还将为B-ALL的新诊断、预后和治疗策略奠定基础。

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.