Abstract
Wnt5a is a ligand of the non-canonical Wnt signaling pathway involved in cell differentiation, motility, and inflammatory response. Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive T-cell malignancies caused by infection of human T-cell leukemia virus type1 (HTLV-1). Among subtypes of ATL, acute-type ATL cells are particularly resistant to current multidrug chemotherapies and show remarkably high cell-proliferative and invasive phenotypes. Here we show a dramatic increase of WNT5A gene expression in acute-type ATL cells compared with those of indolent-type ATL cells. Treatment with IWP-2 or Wnt5a-specific knockdown significantly suppressed cell growth of ATL-derived T-cell lines. We demonstrated that the overexpression of c-Myb and FoxM1 was responsible for the synergistic activation of the WNT5A promoter. Also, a WNT5A transcript variant without the exon4 (the ΔE4-WNT5A mRNA), encoding ΔC-Wnt5 (1-136aa of 380aa), is overexpressed in acute-type ATL cells. The ΔC-Wnt5a is secreted extracellularly and enhances cellular migration/invasion to a greater extent compared with wildtype (WT)-Wnt5a. Moreover, the ΔC-Wnt5a secretion was not suppressed by IWP-2, indicating that this mutant Wnt5a is secreted via a different pathway from the WT-Wnt5a. Taken together, synergistic overexpression of the ΔC-Wnt5a by c-Myb and FoxM1 may be responsible for the malignant phenotype of acute-type ATL cells.
Highlights
Adult T-cell leukemia/lymphoma (ATL) is a T-cell malignancy caused by infection of human T-cell leukemia virus type 1 (HTLV-1) with CD4+ T cells[1]
Please note that the right-hand side panel consists of two pictures from two separated blots for Wnt5a and β-Actin, respectively, which are clearly separated by black frames. (B) The total WNT5A mRNA levels were re-analyzed in gene expression profiling analysis and were confirmed in the quantitative-PCR analysis
We revealed that the total WNT5A mRNA expression level in acute-type ATL cells is more than 100-folds higher than indolent-type ATL cells (Fig. 1C)
Summary
Adult T-cell leukemia/lymphoma (ATL) is a T-cell malignancy caused by infection of human T-cell leukemia virus type 1 (HTLV-1) with CD4+ T cells[1]. In both experiments, malignant ATL cells were isolated as CADM1 + /CD7− CD4+ T cells[26]. The detailed molecular mechanism of its overexpression and effects in ATL cells are still waiting to be elucidated
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