Hematopoietic specific Genes in Stem Cell Development

描述(由申请人提供)：这是一项继续研究RhoGTP酶及其调节蛋白在造血、造血细胞功能和血液系统恶性肿瘤中的作用的建议。RhoGTP酶形成一个蛋白质大家族，调节广泛的一系列基本细胞功能，包括细胞分裂、细胞形状、细胞内运输、细胞骨架组织、基因转录、细胞凋亡、细胞转化和转移。最近发现了RhoGTPase家族的一个新成员，命名为RhoH，它只在造血细胞中特异表达。在一些淋巴瘤和骨髓瘤病例中，RhoH首次被鉴定为与Bcl6非随机易位的融合蛋白，涉及位于染色体4p13的RhoH基因。更重要的是，最近发现在弥漫性大B细胞淋巴瘤(DLCL)中存在高频率的RhoH突变。这是RhoGTP酶参与血液系统恶性肿瘤的第一个例子，以及Rho蛋白家族的临床重要性。这些突变的病理作用仍有待阐明。从最近令人惊讶的发现中得出的重要线索表明，RhoH是其他RhoGTP酶的有效抑制因子。与RhoH是一种“抑制性”蛋白相一致的是，最近的一项发现是，细胞内RhoH的基础水平对于维持T细胞处于非粘附性非活性状态至关重要。RhoH代表了RhoGTP酶和其他相关小G蛋白功能调节的新范式。一个重要的问题是RhoH是做什么的，为什么它的功能与其他RhoGTP酶不同，以及RhoH在淋巴瘤发生中的作用是什么？我们将集中精力回答以下问题：Aim1)RhoH的细胞功能是什么？AIM2)RhoH抑制功能的机制是什么？来自该项目的知识将为一类重要的蛋白质带来新的见解，这些蛋白质越来越多地与癌症的发生和癌症进展有关。这项研究还将使我们能够确定RhoH是否是DLCL亚组中有意义的预测变量，以及它是否可以成为抗癌药物开发的有用靶点。

DESCRIPTION (provided by applicant): This is a proposal to continue the investigation of the role of RhoGTPases and their regulatory proteins in hematopoiesis, hematopoietic cell function and hematopoietic malignancies. The RhoGTPases form a large family of proteins that mediate an extensive array of fundamental cellular function including cell division, cell shape, intra-cellular trafficking, cytoskeletal organization, gene transcription, apoptosis, cellular transformation and metastasis. Recently a new member of the RhoGTPase family have been discovered named RhoH, that is expressed specifically only in hematopoietic cells. RhoH was first identified as a fusion protein with bcl6 in non-random translocations involving the RhoH gene at chromosome 4p13 in some cases of lyrnphoma and myeloma. Even more significant is the recent finding that a high frequency of RhoH mutations exist in the Diffuse Large B-Cell Lymphomas (DLCL). This is the first example of the involvement of a RhoGTPase in hematological malignancies, and the clinical importance of the Rho family of proteins. The pathological role of these mutations remain to be clarified. Important clues derived from recent surprising finding showed that RhoH functions as a potent inhibitor of other RhoGTPases. Consistent with RhoH being an "inhibitory" protein is the recent discovery that a cellular basal level of RhoH is crucial for maintaining T cells in the non-adherant inactive state. RhoH represents a new paradigm for the functional modulation of the RhoGTPases and other related small G-proteins. An important question is what does RhoH do, why does it function differently compared to other RhoGTPases and what is RhoH role in lymphomagenesis? We shall focus our effort to answer the following questions:Aim1) What is the cellular function of RhoH? ; Aim2) What is the mechanism of RhoH inhibitory function?; Aim3) What are the consequences of RhoH mutations in lymphoma? Knowledge from this project will bring new insigths about an important class of proteins that are increasingly implicated in carcinogenesis and cancer progression. The study will also allow us to determine if RhoH is a meaningful variable for prognostication in sub-groups of DLCL and if it can be a useful target for anti-cancer drug development.