Sox7—a potential tumour suppressor in myeloid malignancies

Abstract

Introduction: Sry-related HMG box (SOX) genes are a family of 20 proteins characterised by a highly conserved high-mobility-group (HMG) domain. The sox genes have been shown to regulate diverse processes during embryonic development and neoplastic transformation. However, their roles in haematopoiesis and leukaemogenesis are unclear. Methods: Bone marrow (BM) or peripheral blood samples of patients with myeloid (acute myeloid leukaemia [AML], myelodysplastic syndrome [MDS], chronic myelogenous leukaemia [CML]) and lymphoid (acute lymphoblastic leukaemia [ALL]) malignancies, as well as normal BM and umbilical cord blood (UCB), were prospectively collected. Mononuclear cells (MNC) and CD34+ cells were isolated. Expression of sox genes was evaluated by reverse-transcription polymerase chain reaction (RT-PCR) and western blotting. Methylation of CpG island in sox7 promoter was evaluated by bisulfite sequencing and methylation specific PCR. Leukaemic cell lines were treated with 5-aza-2’deoxycytidine (5-aza-dC). Results: Sox7 was expressed in normal BM MNC (5/14) and UCB CD34+ (6/6) but not in AML (n=33), CML (n=13) and MDS (n=16), as well as four AML-derived cell lines (ML-2, KG-1, NB4, K562). Sox7 was also expressed in 17/23 ALL cases and a cell line derived from precursor B-cell ALL (Nalm-20). None of the other 19 sox genes showed differential expression between normal, myeloid, and lymphoid malignancies. In silico analysis revealed CpG island within the promoter and exon 1 region of sox7 gene. There was CpG hypermethylation as showed by both bisulfite sequencing and methylation-specific PCR. Treating AML-derived cell lines (KG-1, ML-2, and K562) with 5-aza-dC re-expressed sox7 gene. Conclusion: Sox7 exhibited differential gene expression between normal haematopoietic cells and myeloid malignancies and was silenced in the latter due to promoter CpG island methylation. Its role as a tumour suppressor gene should be further evaluated.