Impact of the SCF signaling pathway on leukemia stem cellmediated ATL initiation and progression in an HBZ transgenic mouse model

Wakako Kuribayashi, Kazuya Takizawa, Kenji Sugata, Madoka Kuramitsu, Haruka Momose, Eita Sasaki, Yuki Hiradate, Keiko Furuhata, Yoshihisa Asada, Atsushi Iwama, Masao Matsuoka, Takuo Mizukami, Isao Hamaguchi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)51027-51043
Number of pages17
JournalOncotarget
Volume7
Issue number32
DOIs
Publication statusPublished - 2016 Aug 1
Externally publishedYes

Keywords

  • ATL
  • Cancer stem cell
  • HBZ
  • Leukemia stem cells
  • SCF

ASJC Scopus subject areas

  • Oncology

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