Role of CD45 in Hematopoiesis and Lymphomagenesis

描述(由申请人提供)：淋巴细胞稳态需要协调调节控制增殖、分化和死亡的信号级联反应。这些过程的失调是淋巴系恶性肿瘤发生的必要前提。我们的实验室最近报道了一个新的小鼠模型，该模型包含一个突变，该突变扰乱了受体样蛋白酪氨酸磷酸酶CD45在二聚化过程中的负调控。这些小鼠发生严重的淋巴增殖性疾病，T和B细胞多克隆激活，脾大量肿大，并过早死亡。自身免疫的一个亚群也会形成斑点，包括抗双链DNA抗体的形成和免疫复合体介导的肾小球肾炎。为了确定导致疾病发生的细胞类型，CD45突变小鼠与T、B或T和B细胞缺陷的小鼠交配。B细胞而不是T细胞的基因消除会导致自身免疫性和淋巴增生性疾病的消融。相反，T细胞的缺失会导致淋巴瘤患病率的显著增加。这些观察结果支持这样的假设，即通过二聚化对CD45功能的精确调节对于维持造血系统内的动态平衡是必不可少的。这一功能的破坏可能会导致淋巴增殖、自身免疫和恶性肿瘤的严重后果。这项建议的目标是确定动态平衡崩溃的分子和细胞基础，并确定淋巴瘤发生所需的步骤。第一个目标是测试B细胞--导致疾病发生的内在机制。第二个目标集中在可能促进B细胞增殖的微环境的贡献以及T细胞抑制淋巴肿大的机制。在第三个目标中，生化和基因表达分析被用来研究CD45突变导致疾病的分子基础。阵列CGH和ENU突变被用来开始识别有助于从过度增殖向恶性状态进展的协同事件。这些研究应该为免疫调节、自身免疫和淋巴系统恶性肿瘤之间的联系提供重要的见解，并提高我们对免疫监视机制的理解。

DESCRIPTION (provided by applicant): Lymphocyte homeostasis requires the coordinate regulation of signaling cascades governing proliferation, differentiation, and death. Dysregulation of these processes is a necessary prerequisite for the development of lymphoid malignancies. Our lab recently reported a novel murine model containing a mutation that disrupts the negative regulation of the receptor-like protein tyrosine phosphatase CD45 during dimerization. These mice develop a profound lymphoproliferative disorder with polyclonal activation of T and B cells, massive splenomegaly, and premature death. A subset also develops stigmata of autoimmunity including anti-double stranded DNA antibody formation and immune complex-mediated glomerulonephritis. To define the cell type responsible for disease generation, the CD45 mutant mice were mated to mice deficient in T, B, or T and B cells. Genetic elimination of B cells, but not T cells results in ablation of the autoimmune and lymphoproliferative disorders. In contrast, absence of T cells resulted in a dramatic increase in the prevalence of lymphoma. These observations support the hypothesis that precise regulation of CD45 function by dimerization is essential for the maintenance of homeostasis within the hematopoietic system. Disruption of this function can have profound consequences leading to lymphoproliferation, autoimmunity, and malignancy. The goal of this proposal is to define the molecular and cellular basis for the breakdown of homeostasis and to identify the steps required for the development of lymphomas. The first aim tests B cell-intrinsic mechanisms that contribute to disease initiation. The second aim focuses on contributions from the microenvironment that may enhance B cell expansion and the mechanisms by which T cells inhibit lymphomagenesis. In the third aim, biochemical and gene expression analyses are used to address the molecular basis by which the CD45 mutation contributes to disease. Array CGH and ENU mutagenesis are used to begin to identify cooperating events that contribute to the progression from hyperproliferating to malignant state. These studies should provide important insights into the links between immune regulation, autoimmunity, and lymphoid malignancies as well as improve our understanding of the mechanisms governing immune surveillance.