Suppression of SOX7 by DNA methylation and its tumor suppressor function in acute myeloid leukemia.

ABSTRACT

SOX7 belongs to the SOX (Sry-related high-mobility group [HMG] box) gene family, a group of transcription factors containing in common a HMG box domain. Its role in hematologic 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 or normal bone marrow cells. In cell lines (KG1, ML2, and K562) and in primary CD34(+) AML samples, SOX7 expression could be induced by the DNA demethylating agent 5-aza-2'-deoxycytidine. Overexpression 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 the Wnt/ß-catenin pathway through direct protein binding to ß-catenin, and the antileukemia effects of SOX7 in THP-1 cells were significantly reduced by deletion of its ß-catenin binding site. The results provided unequivocal evidence for a novel tumor suppressor role of SOX7 in AML via a negative modulatory effect on the Wnt/ß-catenin pathway.