title: New mouse model of acute adult T-cell leukemia generated by transplantation of AKT, BCLxL, and HBZ-transduced T cells.
abstract: 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.
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center, Research Institute, Nagoya, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kasugai
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Noriaki
authors.identifier: http://orcid.org/0000-0001-7001-0106
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center, Research Institute, Nagoya, Japan.
authors.forename: Keitaro
authors.identifier: http://orcid.org/0000-0003-1761-6314
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center, Research Institute, Nagoya, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tsuzuki
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines; D004195:Disease Models, Animal; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D012191:Retroviridae Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*; D014161:Transduction, Genetic; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494811:BCL2L1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D016207:Cytokines; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; D051020:bcl-X Protein; D051058:Oncogene Protein v-akt
keywords: AKT; ATL; BCLxL; HBZ; mouse model