Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells

• Published in: Scientific reports Vol. 11; no. 1; p. 4114
• Main Authors: Nakano, Kazumi, Chihara, Yohei, Kobayashi, Seiichiro, Iwanaga, Masako, Utsunomiya, Atae, Watanabe, Toshiki, Uchimaru, Kaoru
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.02.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: c-Myb protein; Cell differentiation; Cell Differentiation - genetics; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Deltaretrovirus - genetics; Gene expression; Gene Expression - genetics; Humans; Inflammation; Invasiveness; Jurkat Cells; Leukemia; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - pathology; Lymphocytes T; Lymphoma; Phenotype; Phenotypes; Signal transduction; T-Lymphocytes - pathology; Transcription; Wnt protein; Wnt Signaling Pathway - genetics; Wnt-5a Protein - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-83613-2

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.