A new model mice for human chronic myelogenous leukemia by the disruption of SPA-1 gene.

Rap1是gtpase Ras家族的成员，根据细胞背景，在增殖或细胞粘附调节中起重要作用。在淋巴造血组织中，SPA-1是主要的Rap1 gtpase激活蛋白。缺乏SPA-1基因的小鼠出现t细胞免疫缺陷的年龄依赖性进展，随后出现一系列晚发性骨髓增殖性疾病，模仿人类慢性骨髓性白血病。在spa -1缺陷小鼠中，Rap1激活失调导致骨髓造血祖细胞扩增增强，但诱导T细胞进行性无反应或能量不足。因此，Rap1及其调控因子SPA-1可以为控制人类血液恶性肿瘤提供独特的分子靶点。spa -1缺乏还引起B1a细胞的年龄依赖性扩增，在腹腔产生抗dsdna和抗核抗体，导致狼疮样自身免疫。在pa -1缺陷小鼠的骨髓B细胞前体中持续激活Rap1，通过激活控制Vκ基因重组的OcaB基因，诱导Vκ基因库明显偏倚和广泛的“部分”受体编辑，从而导致致病性自反应性B1细胞的产生。此外，spa -1缺陷小鼠经常发生优先起源于B1细胞的白血病，并伴有溶血性自身抗体的产生。结果表明，骨髓微环境刺激可显著改变发育中的B细胞抗原受体库的形成，其中rap1信号在其中起重要作用。

Rap1 is a member of the Ras family of GTPases and, depending on the cellular context, has an important role in the regulation of proliferation or cell adhesion. In lympho-hematopoietic tissues, SPA-1 is a principal Rap1 GTPase-activating protein. Mice that were deficient for the SPA-1 gene developed age-dependent progression of T-cell immunodeficiency followed by a spectrum of late onset myeloproliferative disorders, mimicking human chronic myeloid leukemia. Deregulated Rap1 activation in SPA-1-deficient mice caused enhanced expansion of the bone marrow hematopoietic progenitors, but induced progressive unresponsiveness or anergy in T cells. Rap1 and its regulator, SPA-1, could, therefore, provide unique molecular targets for the control of human hematologic malignancy.SPA-1-deficiency also caused the age-dependent expansion of B1a cell producing anti-dsDNA and anti-nuclear antibodies in the peritoneal cavity resulting in lupus-like autoimmunity. Sustained Rap1 activation in the bone marrow B cell precursors in SPA-1-deficient mice induced markedly biased Vκ gene repertoire and extensive "partial" receptor editing by activating OcaB gene controlling Vκ gene recombination, thereby leading to the generation of pathogenic self-reactive B1 cells. Furthermore, SPA-1-deficient mice frequently developed leukemia preferentially of B1 cell origin along with hemolytic autoantibody production. The results suggest that antigen-receptor repertoire formation in developing B cells can be significantly modified by the stimuli from bone marrow microenvironment, in which Rap1-signal plays an important role.