title: Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling.
abstract: The JAK2V617F mutation is associated with distinct myeloproliferative neoplasms, including polycythemia vera (PV) and essential thrombocythemia (ET), but it remains unclear how it generates disparate disorders. By comparing clonally-derived mutant and wild-type cells from individual patients, we demonstrate that the transcriptional consequences of JAK2V617F are subtle, and that JAK2V617F-heterozygous erythroid cells from ET and PV patients exhibit differential interferon signaling and STAT1 phosphorylation. Increased STAT1 activity in normal CD34-positive progenitors produces an ET-like phenotype, whereas downregulation of STAT1 activity in JAK2V617F-heterozygous ET progenitors produces a PV-like phenotype. Our results illustrate the power of clonal analysis, indicate that the consequences of JAK2V617F reflect a balance between STAT5 and STAT1 activation and are relevant for other neoplasms associated with signaling pathway mutations.
authors.affiliation: Cambridge Institute for Medical Research and Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Edwin
authors.initials: E
authors.lastname: Chen
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: Anna L
authors.initials: AL
authors.lastname: Godfrey
authors.forename: Christina A
authors.initials: CA
authors.lastname: Ortmann
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Ana P
authors.initials: AP
authors.lastname: Costa-Pereira
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Ingle
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
mesh_terms: D019943:Amino Acid Substitution; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D016000:Cluster Analysis; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D006801:Humans; D007372:Interferons / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics*; D008533:Megakaryocytes / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics*; D010641:Phenotype; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013920:Thrombocythemia, Essential / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; D007372:Interferons; C507924:JAK2 protein, human; D053614:Janus Kinase 2