Abstract
HTLV-I infection is associated with the development of adult T-cell leukemia (ATL), a malignancy characterized by a high rate of disease relapse and poor survival. Previous studies reported the existence of side population (SP) cells in HTLV-I Tax transgenic mouse models. These studies showed that these ATL-like derived SP cells have both self-renewal and leukemia renewal capacity and represent Cancer Stem Cells (CSC)/Leukemia-Initiating Cells (LIC). Since CSC/LIC are resistant to conventional therapies, a better characterization is needed. We isolated, sorted and characterized SP cells from uncultured PBMCs from ATL patients and from ATL patient-derived cell lines. We then identified several specific signaling pathways activated or suppressed in these cells. Expression of viral gene HBZ and Tax transcriptional activity was also investigated. Using gamma-secretase inhibitor (GSI, Calbiochem) and stably transduced ATL cell lines expressing TET-inducible NOTCH 1 intracellular domain (NICD), we characterized the role of activated NOTCH 1 in the maintenance of the SP cells in ATL. Our studies confirm the existence of SP cells in ATL samples. These cells demonstrate lower activation of NOTCH1 and Tax, and reduced expression of STAT3, β-catenin/Wnt3 and viral HBZ. We further show that PI3K and the NOTCH1 signaling pathway have opposite functions, and constitutive activation of NOTCH1 signaling depletes the pool of SP cells in ATL-derived cell lines. Our results suggest that in ATL, a balance between activation of the NOTCH1 and PI3K signaling pathway is the key in the control of SP cells maintenance and may offer therapeutic opportunities.
Highlights
Limiting dilution transplantation demonstrated that only a small percentage of cells within a cell line population can give rise to tumors in vivo
Characterization of SP cells in adult T-cell leukemia (ATL) fresh samples and patientderived atl cell lines Numerous studies have shown that side population (SP) cells are enriched for cancer stem cells (CSC)/ leukemia-initiating cells (LIC), which have both self-renewal and tumor-regenerating potential [3]
Our results demonstrate the presence of a small percentage of SP cells, from 3% to 5.6%, in all ATL lines and in freshly isolated uncultured ATL primary samples (Figure 1A)
Summary
Limiting dilution transplantation demonstrated that only a small percentage of cells within a cell line population can give rise to tumors in vivo. Numerous studies demonstrate that side population (SP) cells identified by ABC pump-mediated exclusion of Hoechst can be referred to as Leukemia-initiating cells (LIC) or Cancer stem cells (CSC) These cells have the unique ability to regenerate full leukemia and self-renewal of the SP compartment in xenograft models [3]. SP analysis has been used to identify CSC in a wide variety of human solid tumors, including breast, colon, ovarian and hepatic cancers [4,5,6,7] These cells are relatively resistant to commonly used therapies. Previous studies reported the existence of side population (SP) cells in HTLV-I Tax transgenic mouse models These studies showed that these ATL-like derived SP cells have both self-renewal and leukemia renewal capacity and represent Cancer Stem Cells (CSC)/ Leukemia-Initiating Cells (LIC). Since CSC/ LIC are resistant to conventional therapies, a better characterization is needed
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