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New mouse model of acute adult T‐cell leukemia generated by transplantation of AKT, BCLxL, and HBZ‐transduced T cells
Ist Teil von
Cancer science, 2016-08, Vol.107 (8), p.1072-1078
Ort / Verlag
England: John Wiley & Sons, Inc
Erscheinungsjahr
2016
Link zum Volltext
Quelle
Wiley Online Library - AutoHoldings Journals
Beschreibungen/Notizen
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.
Adult T cell leukemia is an intractable cancer and prevalent in Japan. Recently, a comprehensive study of gene mutations in ATL has been reported, but their roles in ATL development are not explored partly due to the lack of an animal model that allows rapid generation of ATL‐like disease. Here, we present such a model mouse, which is a versatile tool to study roles of mutated genes in ATL development.