title: Transcriptional profiling of polycythemia vera identifies gene expression patterns both dependent and independent from the action of JAK2V617F.
abstract: OBJECTIVE
  To understand the changes in gene expression in polycythemia vera (PV) progenitor cells and their relationship to JAK2V617F.
  
  
  METHODS
  Messenger RNA isolated from CD34(+) cells from nine PV patients and normal controls was profiled using Affymetrix arrays. Gene expression change mediated by JAK2V617F was determined by profiling CD34(+) cells transduced with the kinase and by analysis of leukemia cell lines harboring JAK2V617F, treated with an inhibitor.
  
  
  RESULTS
  A PV expression signature was enriched for genes involved in hematopoietic development, inflammatory responses, and cell proliferation. By quantitative reverse transcription-PCR, 23 genes were consistently deregulated in all patient samples. Several of these genes such as WT1 and KLF4 were regulated by JAK2, whereas others such as NFIB and EVI1 seemed to be deregulated in PV by a JAK2-independent mechanism. Using cell line models and comparing gene expression profiles of cell lines and PV CD34(+) PV specimens, we have identified panels of 14 JAK2-dependent genes and 12 JAK2-independent genes. These two 14- and 12-gene sets could separate not only PV from normal CD34(+) specimens, but also other MPN such as essential thrombocytosis and primary myelofibrosis from their normal counterparts.
  
  
  CONCLUSIONS
  A subset of the aberrant gene expression in PV progenitor cells can be attributed to the action of the mutant kinase, but there remain a significant number of genes characteristic of the disease but deregulated by as yet unknown mechanisms. Genes deregulated in PV as a result of the action of JAK2V617F or independent of the kinase may represent other targets for therapy.
authors.affiliation: Translational Research Sciences, Hoffmann-La Roche, Inc., Nutley, NJ, USA.
authors.forename: Windy
authors.initials: W
authors.lastname: Berkofsky-Fessler
authors.forename: Monica
authors.initials: M
authors.lastname: Buzzai
authors.forename: Marianne K-H
authors.initials: MK
authors.lastname: Kim
authors.forename: Steven
authors.initials: S
authors.lastname: Fruchtman
authors.forename: Vesna
authors.initials: V
authors.lastname: Najfeld
authors.forename: Dong-Joon
authors.initials: DJ
authors.lastname: Min
authors.forename: Fabricio F
authors.initials: FF
authors.lastname: Costa
authors.forename: Jared M
authors.initials: JM
authors.lastname: Bischof
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Soares
authors.forename: Melanie Jane
authors.initials: MJ
authors.lastname: McConnell
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Raffaele
authors.initials: R
authors.lastname: Calogero
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
mesh_terms: D019943:Amino Acid Substitution; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016000:Cluster Analysis; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011087:Polycythemia Vera / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D018952:Antigens, CD34; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D004921:Erythropoietin; D053614:Janus Kinase 2