HOME HELP FEEDBACK ARCHIVE SUBSCRIPTIONS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Fouroclas et al. Supplementary appendix Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Fourouclas, N. Articles by Bench, A. J. PubMed PubMed Citation Articles by Fourouclas, N. Articles by Bench, A. J.

Methylation of the suppressor of cytokine signaling 3 gene (SOCS3) in myeloproliferative disorders

¹ University of Cambridge, Department of Haematology, Cambridge Institute for Medical Research, Cambridge, CB2 0XY
² Academic Unit of Haematology, School of Medicine and Biomedical Science, Beech Hill Road, Sheffield, S10 2RX
³ Department of Haematology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ
⁴ Department of Haematology, Russell’s Hall Hospital, Dudley, DY1 2HQ and
⁵ Department of Haematology, St Thomas’s Hospital, London, SE1 7EH, UK

Correspondence: Anthony J Bench, Haemato-oncology Diagnostic Service, Department of Haematology, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ, UK. E-mail:anthony.bench{at}adden-brookes.nhs.uk

ABSTRACT

Background: The JAK2 V617F mutation can be found in patients with polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Mutation or methylation of other components of JAK/STAT signaling, such as the negative regulators suppressor of cytokine signaling 1 (SOCS1) and SOCS3, may contribute to the pathogenesis of both JAK2 V617F positive and negative myeloproliferative disorders.

Design and Methods: A cohort of myeloproliferative disorders patients was assessed for acquired mutations, aberrant expression and/or CpG island hypermethylation of SOCS1 and SOCS3.

Results: No mutations were identified within the coding region of either gene in 73 patients with myeloproliferative disorders. No disease-specific CpG island methylation of SOCS1 was observed. SOCS1 expression was raised in myeloproliferative disorders granulocytes but the level was independent of JAK2 V617F status. Hypermethylation of the SOCS3 promoter was identified in 16 of 50 (32%) patients with idiopathic myelofibrosis but not in patients with essential thrombocythemia, polycythemia vera or myelofibrosis preceded by another myeloproliferative disorders. Confirmation of methylation status was validated by nested polymerase chain reaction and/or bisulphite sequencing. SOCS3 transcript levels were highest in patients with poly-cythemia vera and other JAK2 V617F positive myeloproliferative disorders, consistent with SOCS3 being a target gene of JAK2/STAT5 signaling. There was a trend towards an association between SOCS3 methylation and lower SOCS3 expression in JAK2 V617F negative patients with idiopathic myelofibrosis but not in JAK2 V617F positive ones. Finally, SOCS3 methylation was not significantly correlated with survival or other clinical variables.

Conclusions: SOCS3 promoter methylation was detected in 32% of patients with idiopathic myelofibrosis suggesting a possible role for SOCS3 methylation in this disorder. The pathogenetic consequences of SOCS3 methylation in idiopathic myelofibrosis remain to be fully elucidated.

Key words: SOCS3, SOCS1, hypermethylation, myeloproliferative disorders.