title: Two clinical phenotypes in polycythemia vera.
abstract: BACKGROUND
  Polycythemia vera is the ultimate phenotypic consequence of the V617F mutation in Janus kinase 2 (encoded by JAK2), but the extent to which this mutation influences the behavior of the involved CD34+ hematopoietic stem cells is unknown.
  
  
  METHODS
  We analyzed gene expression in CD34+ peripheral-blood cells from 19 patients with polycythemia vera, using oligonucleotide microarray technology after correcting for potential confounding by sex, since the phenotypic features of the disease differ between men and women.
  
  
  RESULTS
  Men with polycythemia vera had twice as many up-regulated or down-regulated genes as women with polycythemia vera, in a comparison of gene expression in the patients and in healthy persons of the same sex, but there were 102 genes with differential regulation that was concordant in men and women. When these genes were used for class discovery by means of unsupervised hierarchical clustering, the 19 patients could be divided into two groups that did not differ significantly with respect to age, neutrophil JAK2 V617F allele burden, white-cell count, platelet count, or clonal dominance. However, they did differ significantly with respect to disease duration; hemoglobin level; frequency of thromboembolic events, palpable splenomegaly, and splenectomy; chemotherapy exposure; leukemic transformation; and survival. The unsupervised clustering was confirmed by a supervised approach with the use of a top-scoring-pair classifier that segregated the 19 patients into the same two phenotypic groups with 100% accuracy.
  
  
  CONCLUSIONS
  Removing sex as a potential confounder, we identified an accurate molecular method for classifying patients with polycythemia vera according to disease behavior, independently of their JAK2 V617F allele burden, and identified previously unrecognized molecular pathways in polycythemia vera outside the canonical JAK2 pathway that may be amenable to targeted therapy. (Funded by the Department of Defense and the National Institutes of Health.).
authors.affiliation: From the Division of Hematology, Department of Medicine (J.L.S., D.M.W., O.R., A.R.M.), Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center (M.C.), and the Basic Science Institute (C.C.T.), Johns Hopkins University School of Medicine, Baltimore; the Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago (C.J.); and the Department of Mathematics and Statistics, College of New Jersey, Ewing (M.F.O.).
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Spivak
authors.forename: Michael
authors.initials: M
authors.lastname: Considine
authors.forename: Donna M
authors.initials: DM
authors.lastname: Williams
authors.forename: Conover C
authors.initials: CC
authors.lastname: Talbot
authors.forename: Ophelia
authors.initials: O
authors.lastname: Rogers
authors.forename: Alison R
authors.initials: AR
authors.lastname: Moliterno
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.forename: Michael F
authors.initials: MF
authors.lastname: Ochs
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34; D001772:Blood Cell Count; D015986:Confounding Factors, Epidemiologic; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011087:Polycythemia Vera / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors
chemical_list: D018952:Antigens, CD34; C507924:JAK2 protein, human; D053614:Janus Kinase 2