Establishment of a leukemia model mouse by introducing mutated FLT3 gene

迄今为止，强烈需要开发一种新的治疗策略，其靶向与肿瘤发生相关的分子。在白血病中，众所周知，全反式维甲酸和伊马替尼分别对急性早幼粒细胞白血病和慢性粒细胞白血病或伴有BCR/ABL易位的急性淋巴细胞白血病具有上级作用。由于FLT 3基因突变是一个不良预后因素，约30%的成人AML涉及FLT 3基因突变，因此，针对突变FLT 3的新型治疗药物的开发将成功地为具有不良预后因素的AML患者带来巨大益处。然而，为了分析来自突变的FLT 3的生物学效应和评价FLT 3靶向剂的体内药理学效应，需要通过导入突变的FLT 3基因来建立白血病模型小鼠。本研究试图通过诱导突变型FLT 3基因转基因小鼠，建立FLT 3基因突变型转基因小鼠骨髓移植模型。 ...更多信息 将突变的FLT 3基因导入小鼠造血干细胞，构建了3种突变的FLT 3基因表达载体，分别含SR-α、β-actin和cathepsin-G启动子，制备了突变的FLT 3转基因小鼠。虽然突变的FLT 3在SR-α启动子下的转基因是成功的，但是我们不能获得创始者，因为FLT 3的高表达导致生殖细胞功能受到干扰。另一方面，我们可以建立几个创始人表达突变FLT 3基因的β-actin和组织蛋白酶-G启动子。尽管这些菌株表达突变的FLT 3 mRNA，但突变的FLT 3的蛋白产物是微弱的。然而，一些菌株发展为CLL样疾病。有报道称，移植了表达突变FLT 3的干细胞的小鼠发生非克隆性骨髓增生性疾病，但不发生AML。因此，认为严格调节突变的FLT 3的表达水平对于AML模型小鼠的产生是重要的。少

To date, the development of a novel therapeutic strategy, which targets the molecule associated with tumorigenesis, is strongly required. In leukemia, it is well known that all-trans retinoic acid and imatinib bring the superior effects to acute promyelocytic leukemia and chronic myeloid leukemia or acute lymphoblastic leukemia with the BCR/ABL translocation, respectively. Since FLT3 gene mutation is a poor prognostic factor which is involved in about 30% of the adult AML, the development of the novel therapeutic agents, which target to mutated FLT3, will succeed in the great benefits to the AML patients with poor prognostic factors. However, it is necessary to establish the leukemia-model mouse by introducing the mutated FLT3 gene for analyzing the biological effects from the mutated FLT3 and evaluating the pharmacological effects of the FLT3-targeted agents in vivo. In this study, we tried to establish the mutated FLT3 gene transgenic mouse and bone marrow transplantation model by in … More troducing the mutated FLT3 gene into mouse hematopoietic stem cells.We constructed three kinds of mutated FLT3-expression vectors, which contained SR-α, β-actin and cathepsin-G promoter, respectively and subjected to produce the mutated FLT3-transgenic mice. Although the transgene of the mutated FLT3 was successful under the SR-α promoter, we could not obtained the founder because the generative cell function was disturbed due to the high expression of FLT3. On the other hand, we could established several founders expressing mutant FLT3 gene under β-actin and cathepsin-G promoters. Although these strains expressed mutated FLT3 mRNA, protein products of mutated FLT3 were faint. However, several strains developed CLL like disease. It has been reported that mice transplanted with mutant FLT3 expresseing stem cells developed non-clonal myeloproliferative disease, but not AML. Therefore, it is thought to be important for production of an AML model mouse to strictly regulate the expression level of mutated FLT3. Less