title: JAK2V617F-negative ET patients do not display constitutively active JAK/STAT signaling.
abstract: OBJECTIVE
  Presence of the JAK2V617F mutation in only 40% to 60% of patients with essential thrombocythemia (ET) underscores the heterogeneity of this myeloproliferative disorder (MPD). Several distinct mutations, either in JAK2 (exon 12) or in c-Mpl (W515L) have been described in subsets of other MPDs, polycythemia vera, and idiopathic myelofibrosis. Analogous to JAK2,V617F these mutations cause constitutive JAK2 and signal transducer and activation of transcription (STAT) activation. It has therefore been proposed that constitutive activation of the JAK/STAT pathway underlies the molecular etiology of all MPDs. We investigated the alternative hypothesis that distinct alterations, separate from the JAK/STAT signal transduction pathway, underlie a subset of JAK2V617F-negative ET.
  
  
  METHODS
  cDNA microarrays and quantitative reverse transcriptase polymerase chain reactions were used to compare gene expression in 40 ET patients with and without the JAK2V617F mutation.
  
  
  RESULTS
  Unsupervised clustering of gene-expression patterns in ET patients revealed two distinct subclasses of patients. These subclasses differed in presence or absence of the JAK2V617F mutation. Patients lacking the JAK2V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and suppressor of cytokine signaling-2. In addition, JAK2V617F-negative patients showed lower levels of STAT3 phosphorylation.
  
  
  CONCLUSIONS
  These data demonstrate that a large proportion of JAK2V617F-negative ET patients do not display constitutive JAK/STAT signaling. Hence, we propose that alterations in different signal transduction pathways can lead to the clinical phenotype of ET. Elucidation of novel ET-inducing changes will facilitate both a molecular classification of ET and development of rationally designed therapies.
authors.affiliation: Department of Experimental Anaesthesiology, University Hospital Freiburg, Center for Clinical Research, Freiburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Schwemmers
authors.forename: Britta
authors.initials: B
authors.lastname: Will
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Waller
authors.forename: Khadija
authors.initials: K
authors.lastname: Abdulkarim
authors.forename: Peter
authors.initials: P
authors.lastname: Johansson
authors.forename: Björn
authors.initials: B
authors.lastname: Andreasson
authors.forename: Heike L
authors.initials: HL
authors.lastname: Pahl
mesh_terms: D004789:Enzyme Activation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D051573:Proto-Oncogene Proteins c-pim-1 / Q000032:analysis / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000378:metabolism
chemical_list: C106643:SOCS2 protein, human; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D053614:Janus Kinase 2; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1