title: Methylation of the suppressor of cytokine signaling 3 gene (SOCS3) in myeloproliferative disorders.
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.
  
  
  METHODS
  A cohort of patients with myeloproliferative disorders 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 disorder 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 disorder. Confirmation of methylation status was validated by nested polymerase chain reaction and/or bisulphite sequencing. SOCS3 transcript levels were highest in patients with polycythemia 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.
authors.affiliation: Haemato-oncology, Diagnostic Service, Department, of Haematology, Addenbrooke's, Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
authors.forename: Nasios
authors.initials: N
authors.lastname: Fourouclas
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Gilby
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Boyd
authors.forename: Anne C
authors.initials: AC
authors.lastname: Goodeve
authors.forename: David
authors.initials: D
authors.lastname: Bareford
authors.forename: Claire N
authors.initials: CN
authors.lastname: Harrison
authors.forename: John T
authors.initials: JT
authors.lastname: Reilly
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bench
mesh_terms: D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D017931:DNA Primers; D015226:Dinucleoside Phosphates / Q000235:genetics; D006098:Granulocytes / Q000502:physiology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000378:metabolism*; D011087:Polycythemia Vera / Q000235:genetics; D055728:Primary Myelofibrosis / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D013920:Thrombocythemia, Essential / Q000235:genetics
chemical_list: D004247:DNA; D017931:DNA Primers; D015226:Dinucleoside Phosphates; D053614:Janus Kinase 2; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C015772:CpG dinucleotide; C507924:JAK2 protein, human