title: Impact of the SCF signaling pathway on leukemia stem cell-mediated ATL initiation and progression in an HBZ transgenic mouse model.
abstract: Adult T-cell leukemia (ATL) is a malignant disease caused by human T-lymphotropic virus type 1. In aggressive ATL, the response to chemotherapy is extremely poor. We hypothesized that this poor response is due to the existence of chemotherapy-resistant cells, such as leukemic stem cells. Previously, we successfully identified an ATL stem cell (ATLSC) candidate as the c-kit+/CD38-/CD71- cells in an ATL mouse model using Tax transgenic mice. Here, with a new ATL mouse model using HBZ-transgenic mice, we further discovered that the functional ATLSC candidate, which commonly expresses c-kit, is drug-resistant and has the ability to initiate tumors and reconstitute lymphomatous cells. We characterized the ATLSCs as c-kit+/CD4-/CD8- cells and found that they have a similar gene expression profile as T cell progenitors. Additionally, we found that AP-1 gene family members, including Junb, Jund, and Fosb, were up-regulated in the ATLSC fraction. The results of an in vitro assay showed that ATLSCs cultured with cytokines known to promote stem cell expansion, such as stem cell factor (SCF), showed highly proliferative activity and maintained their stem cell fraction. Inhibition of c-kit-SCF signaling with the neutralizing antibody ACK2 affected ATLSC self-renewal and proliferation. Experiments in Sl/Sld mice, which have a mutation in the membrane-bound c-kit ligand, found that ATL development was completely blocked in these mice. These results clearly suggest that the c-kit-SCF signal plays a key role in ATLSC self-renewal and in ATL initiation and disease progression.
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan.|Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.|Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Kuribayashi
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takizawa
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugata
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Kuramitsu
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Momose
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan.
authors.forename: Eita
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hiradate
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Furuhata
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Asada
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Mizukami
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Hamaguchi
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012191:Retroviridae Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit
keywords: ATL; HBZ; SCF; cancer stem cell; leukemia stem cells