对家族性白血病的深入研究有助于揭示白血病发病机制。本项目采用定位克隆策略，在一个急性髓系白血病（AML）高发家系中发现了TGM6基因点突变，该基因突变与疾病表型共分离，为该家系AML的致病突变，但其在白血病发病中的作用尚不清楚。将用生物信息学预测TGM6突变对其结构、功能的影响；检测与验证散发及家系AML中TGM6的突变情况，绘制TGM6突变图谱，明确TGM6突变与AML的关系及意义；在分子水平上，检测TGM6突变对其转谷氨酰胺酶、GTP酶及蛋白激酶活性的影响；细胞水平上，观测TGM6突变对细胞增殖、分化、凋亡等的影响；动物水平上，构建过表达野生型与突变型TGM6的小鼠骨髓移植模型，观察TGM6过表达及突变对小鼠生存期、骨髓细胞表型等的影响及裸鼠中的致瘤性。从分子、细胞、动物水平研究TGM6基因及其突变体的功能，以揭示TGM6基因突变在白血病发生发展中的作用机制，为开发靶向药物奠定理论基础

Further study of familial leukemia will shed lights on the mechanism of leukemogenesis. By the positional cloning strategies ,a causative point mutation of TGM6 in an acute myeloid leukemia(AML) predisposition family has been previously identified, which was proved to be co-segregated with the phenotype and maybe the culprit mutation. However, its role in leukemogenesis remains obscure. For the next investigation, bioinformatics methodologies will be employed to analyze the mutation's influence on the structure and function of TGM6. Screening and validation of TGM6 mutations in sporadic patients and other AML pedigrees aims to delineate its mutation map and define its relationship and significance of AML. Moreover, a comprehensive research of TGM6 and its mutation will be performed in three separate aspects, including the detection of their influence on the activity of transglutaminase, GTPase and protein kinase at the molecular level;the monitoring of their influence on cell proliferation, differentiation, apoptosis and intracellular position at the cellular level;the observation of their influence on survival time and bone marrow cell phenotypes of the mice as well as tumorigenesis of the nude mice at the animal levels, through constructing bone marrow transplantation murine model of wild-tyoe TGM6 over-expression and mutative TGM6 expression respectively. Thus,the functional study of TGM6 and its mutation at the molecular, cellular and animal levels will reveal their roles in leukemogenesis, and meanwhile provides the necessary theoretical basis for targed drugs development.