New mouse model of acute adult T-cell leukemia generated by transplantation of AKT, BCLxL, and HBZ-transduced T cells
New mouse model of acute adult T-cell leukemia generated by transplantation of AKT, BCLxL, and HBZ-transduced T cells
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DOI：
10.1111/cas.12974
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发表时间：
2016-08-01
期刊：
影响因子：
5.7
通讯作者：
Tsuzuki, Shinobu
中科院分区：
文献类型：
--
作者：
Kasugai, Yumiko;Yoshida, Noriaki;Tsuzuki, Shinobu
成人T细胞白血病/淋巴瘤（ATL）在人类T细胞白血病病毒1型（HTLV-1）携带者中发展。虽然HTLV-1编码的HBZ基因是关键参与，HBZ单独是不够的，需要额外的，合作的“命中”ATL的发展。正在定义候选合作命中，但缺乏与HBZ合作快速探索其在ATL开发中的作用的方法。在这里，我们提出了一种新的急性型ATL的小鼠模型，可以通过移植在体外诱导的T细胞，已逆转录病毒转导HBZ和两个合作基因，BCLxL和AKT，到小鼠中迅速产生。HBZ和BCLxL/AKT的共转导允许这些T细胞在不存在细胞因子（Flt 3-配体和白细胞介素-7）的情况下在体外生长，这在任何两个基因组合的情况下都不会发生。虽然移植的T细胞是用不同基因组合转导的细胞的混合物，但小鼠中产生的肿瘤由HBZ/BCLxL/AKT三重转导的T细胞组成，显示出三种基因的协同作用。ATL的遗传/表观遗传景观最近才被阐明，并且在ATL发病机制中额外的“命中”的作用仍有待探索。我们的模型提供了一个多功能的工具来检查这些命中的作用，与HBZ合作，在急性ATL的发展。
Adult T-cell leukemia/lymphoma (ATL) develops in human T-cell leukemia virus type 1 (HTLV-1) carriers. Although the HTLV-1-encoded HBZ gene is critically involved, HBZ alone is insufficient and additional, cooperative "hits" are required for the development of ATL. Candidate cooperative hits are being defined, but methods to rapidly explore their roles in ATL development in collaboration with HBZ are lacking. Here, we present a new mouse model of acute type ATL that can be generated rapidly by transplanting in vitro-induced T cells that have been retrovirally transduced with HBZ and two cooperative genes, BCLxL and AKT, into mice. Co-transduction of HBZ and BCLxL/AKT allowed these T cells to grow in vitro in the absence of cytokines (Flt3-ligand and interleukin-7), which did not occur with any two-gene combination. Although transplanted T cells were a mixture of cells transduced with different combinations of the genes, tumors that developed in mice were composed of HBZ/BCLxL/AKT triply transduced T cells, showing the synergistic effect of the three genes. The genetic/epigenetic landscape of ATL has only recently been elucidated, and the roles of additional "hits" in ATL pathogenesis remain to be explored. Our model provides a versatile tool to examine the roles of these hits, in collaboration with HBZ, in the development of acute ATL.