| Research Abstract |
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
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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
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