Study of Leukemogenesis in Adult T-Cell Leukemia using SCID mouse model

众所周知，HTLV-I是一种致瘤性C型逆转录病毒，可引起成人T细胞白血病(ATL)。HTLV-I是第一种引起人类恶性肿瘤的人类逆转录病毒。本实验旨在通过动物模型研究白血病的发生机制和针对ATL的治疗策略。除了SCID小鼠免疫球蛋白重排和T细胞受体基因重排的常染色体隐性突变导致它们缺乏功能性T和B淋巴细胞外，通过将SCID突变突变的任何一种回交到其他突变的小鼠上，培育出新的免疫缺陷小鼠。人T淋巴细胞在新的免疫缺陷小鼠品系中重组。我们利用免疫缺陷小鼠建立了HTLV-I感染系统，并用人T细胞淋巴瘤杀死小鼠。免疫缺陷小鼠的人T细胞淋巴瘤与ATL白血病细胞非常相似，我们检测到IL-2、IL-10、干扰素-γ和M-CSF等细胞因子基因的活性表达，尽管所有肿瘤细胞都含有HTLV-I全序列，但Tax基因的表达很低。这一结果可能表明，TAX基因在ATL细胞的发育过程中是必需的，而不是维持体内ATL细胞的增殖所必需的。利用免疫缺陷小鼠体内白血病的发生需要揭示哪些因素参与了白血病的发生。

It is well known that HTLV-I is an oncogenic type C retrovirus for one of the T cell malignancies, adult T-cell leukemia (ATL). HTLV-I is a first human retrovirus which causes the human malignant tumor. Our experiment has been designed to investigate mechanism of leukemogenesis and develop therapy strategy against the ATL using an animal model.In addition of scid mice which have an autosomal recessive mutation of the rearrangement on immunoglobulin and T-cell receptor genes resulting that they lack functional T and B lymphocytes, new immunodeficient mice were developed by either backcrossing of scid mutant onto the other mutant mice. Human T lymphocytes were reconstituted in the new immunodeficient mouse strains. Using the immunodeficient mice we developed the infection system of HTLV-I and the mice were killed by human T-cell lymphoma.The human T-cell lymphoma in the immunodeficient mice was very similar to ATL leukemic cells and we detected active cytokine gene expression such as IL-2, IL-10, IFN-gamma, and M-CSF.Although all tumor cells contained entire HTLV-I sequence, the expression of tax gene was low. This results may implicate that tax gene is required in development of ATL cells and is not essential to maintain the proliferation of the ATL cells in vivo. It is necessary to reveal what kind of factors involve in the leukemogenesis in vivo using the immunodeficient mice.