Suppression of SOX7 by DNA methylation and its tumor suppressor function in acute myeloid leukemia
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels le gène SOX7 exerce une fonction de suppresseur de tumeurs dans la leucémie myéloïde aiguë
SOX7 expression is silenced in common myeloid malignancies.SOX7 interacts directly with β-catenin and regulates the Wnt pathway in acute myeloid leukemia. SOX7 belongs to the SOX (Sry-related HMG box) gene family, a group of transcription factors containing in common a High-Mobility-Group (HMG) box domain. Its role in hematological malignancies and in particular acute myeloid leukemia (AML) is completely unknown. Here we showed that SOX7 expression was regulated by DNA hypermethylation in AML but not in acute lymphoblastic leukemia (ALL) or normal bone marrow (BM) cells. In both cell lines (KG1, ML2, K562) and primary CD34+ AML samples, SOX7 expression could be induced by DNA demethylating agent 5-aza-2'-deoxycytidine. Over-expression of SOX7 in K562 cells inhibited cell proliferation with cell cycle delay in S/G2/M phases and reduced clonogenic activity. Apoptosis was unaffected. Ectopic expression of SOX7 in K562 and THP-1 cells as well as primary CD33+CD34+ AML cells abrogated leukemia engraftment in xenogeneic transplantation. SOX7 expression inhibited wnt/β-catenin pathway through direct protein binding to β-catenin and the anti-leukemia effects of SOX7 in THP-1 cells were significantly reduced by deletion of its β-catenin binding site. The results provided unequivocal evidence for a novel tumor suppressor role of SOX7 in AML via a negative modulatory effect on wnt/β-catenin pathway.