Down-regulation of TCF8 is involved in the leukemogenesis of adult T-cell leukemia/lymphoma

Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1-mediated growth suppression in adult T-cell leukemia/lymphoma

“…To investigate the role that ZEB1 has in TGF-b1 signaling in CTLL2 cells, we transfected the cells with a ZEB1 shRNA vector (CTLL2-shZEB1) or a luciferase shRNA vector, which served as a control (CTLL2-shLuc), and examined the TGF-b1-induced transcription of Smad6, Smad7, PAI-1 and p21 by semiquantitative and quantitative RT-PCR. As previously reported, survival rates of CTLL2-shZEB1 cells increased to 60% after treatment with TGF-b1 (data not shown, Hidaka et al, 2008). As shown in Figure 6b, treatment of TGF-b1 immediately induced Smad6 and Smad7 transcription as early as 30 min, and PAI-1 mRNA was induced 1 h after TGF-b1 treatment.…”

“…ATLL cells are derived from the malignant clonal expansion of an HTLV-1-infected CD4 þ T lymphocyte that has accumulated genetic lesions, including the activation of oncogenes or inactivation of tumorsuppressor genes (Tsukasaki et al, 2001). A previous study from our laboratory discovered these genetic lesions by spectral karyotyping with a high-density single-nucleotide polymorphism array and comparative genomic hybridization in ATLL; we found that the T-cell transcription factor (TCF8)/zinc-finger E-box binding homeobox 1 (ZEB1) was a candidate tumor suppressor in ATLL (Hidaka et al, 2008).…”

“…We previously reported that ZEB1 expression was downregulated and functioned as a possible tumor suppressor in a majority of ATLL cells (Hidaka et al, 2008). ZEB1 has been reported to bind Smad3 and enhance TGF-b1 signaling, and the resistance of HTLV-1-infected T cells and ATLL cells to TGF-b1-mediated growth inhibition is one of the most prominent characteristics of ATLL.…”

“…To examine how ZEB1 expression modulates TGF-b1 signaling, we used the murine interleukin-2 (IL-2)-dependent T-lymphoma cell line CTLL2, which has high expression of ZEB1 and low or no expression of Smad7, for this experiment. CTLL2 is known to be one of the T-cell lines that is highly responsive the treatment of TGF-b1, showing a decrease in cell viability to approximately 40%, compared to the control 2 days after TGF-b1 stimulation (Inge et al, 1992;Hidaka et al, 2008). To investigate the role that ZEB1 has in TGF-b1 signaling in CTLL2 cells, we transfected the cells with a ZEB1 shRNA vector (CTLL2-shZEB1) or a luciferase shRNA vector, which served as a control (CTLL2-shLuc), and examined the TGF-b1-induced transcription of Smad6, Smad7, PAI-1 and p21 by semiquantitative and quantitative RT-PCR.…”

“…One such mechanism might be associated with aberrant expression of MEL1S (Yoshida et al, 2004), which was originally isolated as the gene that was transcriptionally activated by t(1;3)(p36;q21) in acute myeloid leukemia (Mochizuki et al, 2000). We previously reported that ZEB1 expression was downregulated in a majority of ATLL cells (Hidaka et al, 2008). Furthermore, ZEB1-mutant mice frequently developed CD4 þ T-cell lymphomas and/or leukemias, suggesting that ZEB1 may have a tumor suppressive role in ATLL.…”