Suppressor of cytokine signalling‐1 gene silencing in acute myeloid leukaemia and human haematopoietic cell lines

Abstract

Summary The aim of this study was to investigate whether the suppressor of cytokine signalling (SOCS)‐1 can act as a tumour suppressor when functioning as a negative regulator of the Janus family tyrosine kinases (JAKs), which have been reported to play important roles in leukaemogenesis. For this purpose, we carried out molecular analysis of the SOCS‐1 gene in human acute myeloid leukaemia (AML) and human haematopoietic cell lines. Sequencing alterations in the coding region were found in two of 90 primary AML samples and one of 17 cell lines. Hypermethylation of the SOCS‐1 gene was also observed in 72% of primary cases and 52% of cell lines and aberrant methylation strongly correlated with reduced expression. Transfection of SOCS‐1 into Jurkat cells harbouring the mutation and methylation suppressed cell growth at a low serum concentration. These findings indicate that SOCS‐1 is frequently silenced in haematopoietic malignancies, mainly as a result of hypermethylation, and suggest that SOCS‐1 may be able to function as a tumour suppressor.

How frequent is SOCS1 methylation in acute myeloid leukaemia?

“…These results were confirmed by sequencing, suggesting that methylation within SOSC1 exon 2 might not be necessarily involved in regulation of gene transcription. The lack of impact of SOSC1 exon 2 methylation on gene expression was also shown by Watanabe et al (2004). In the two cell lines HL60 and U937, where complete methylation of CpG islands within SOCS1 exon 2 was present, there was still a substantial expression of SOCS1 (Fig 1, Watanabe et al, 2004), thus showing an incomplete correlation between methylation and gene silencing.…”

“…Later reports, however, focussed on CpG islands in the 5¢UTR. We have recently shown that MSP with primers located in exon 2, as described by Watanabe et al (2004), detected methylation in five of 12 normal peripheral blood and two of three normal marrow samples . These results were confirmed by sequencing, suggesting that methylation within SOSC1 exon 2 might not be necessarily involved in regulation of gene transcription.…”

“…A recent article by Watanabe et al (2004) described aberrant methylation of the suppressor of cytokine signalling (SOCS)-1 gene in 72% of primary acute myeloid leukaemia samples, and 52% of leukaemia cell lines. In their experiment, they employed methylation specific polymerase chain reaction (MSP) with a pair of primers flanking the CpG islands inside exon 2 of SOCS1.…”

“…CpG islands exist both in the untranslated region (UTR) 5¢ to, as well as inside the coding region of, exon (Fig 1). Aberrant methylation of CpG islands in these two regions and its relationship to SOCS1 suppression have been studied Chen et al, 2003;Fukushima et al, 2003;Galm et al, 2003;Liu et al, 2003;Nagai et al, 2003;Watanabe et al, 2004) (Fig 1). Initial reports investigated the CpG islands within exon 2.…”

Epigenetic regulation of signal transducer and activator of transcription 3 in acute myeloid leukemia

“…The majority of the patients studied by the second group, whose samples demonstrated hypermethylated SHP1, had leukemia characterized by t(8;21) or inv (16), also known as core factor binding leukemia (Table 4). SOCS1 hypermethylation was frequently detected in AML patient samples by two groups [64,65] but not by two other groups [58,63] (Table 4). Only the first group [64] reported correlation with karyotype (Table 4).…”