Impact of the SCF signaling pathway on leukemia stem cell-mediated ATL initiation and progression in an HBZ transgenic mouse model
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Wakako Kuribayashi1,2,3, Kazuya Takizawa1, Kenji Sugata4, Madoka Kuramitsu1, Haruka Momose1, Eita Sasaki1, Yuki Hiradate1, Keiko Furuhata1, Yoshihisa Asada3, Atsushi Iwama2, Masao Matsuoka4, Takuo Mizukami1,* and Isao Hamaguchi1,*
1 Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, Tokyo, Japan
2 Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
3 Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
4 Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan
* These authors have contributed equally to this study as the corresponding authors
Takuo Mizukami, email:
Keywords: ATL, HBZ, leukemia stem cells, cancer stem cell, SCF
Received: May 23, 2016 Accepted: June 01, 2016 Published: June 21, 2016
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.
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