title: The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation.
abstract: Although a large proportion of patients with polycythemia vera (PV) harbor a valine-to-phenylalanine mutation at amino acid 617 (V617F) in the JAK2 signaling molecule, the stage of hematopoiesis at which the mutation arises is unknown. Here we isolated and characterized hematopoietic stem cells (HSC) and myeloid progenitors from 16 PV patient samples and 14 normal individuals, testing whether the JAK2 mutation could be found at the level of stem or progenitor cells and whether the JAK2 V617F-positive cells had altered differentiation potential. In all PV samples analyzed, there were increased numbers of cells with a HSC phenotype (CD34+CD38-CD90+Lin-) compared with normal samples. Hematopoietic progenitor assays demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level. The JAK2 V617F mutation was detectable within HSC and their progeny in PV. Moreover, the aberrant erythroid potential of PV HSC was potently inhibited with a JAK2 inhibitor, AG490.
authors.affiliation: Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Catriona H M
authors.initials: CH
authors.lastname: Jamieson
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Durocher
authors.forename: Mark P
authors.initials: MP
authors.lastname: Chao
authors.forename: M Rajan
authors.initials: MR
authors.lastname: Mariappan
authors.forename: Marla
authors.initials: M
authors.lastname: Lay
authors.forename: Carol
authors.initials: C
authors.lastname: Jones
authors.forename: James L
authors.initials: JL
authors.lastname: Zehnder
authors.forename: Stan L
authors.initials: SL
authors.lastname: Lilleberg
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D019943:Amino Acid Substitution / Q000235:genetics; D018952:Antigens, CD34 / Q000032:analysis; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000201:enzymology; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D053614:Janus Kinase 2; D010649:Phenylalanine / Q000737:chemistry / Q000235:genetics; D017354:Point Mutation; D011087:Polycythemia Vera / Q000201:enzymology / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D018800:Thy-1 Antigens / Q000032:analysis; D020032:Tyrphostins / Q000494:pharmacology; D014633:Valine / Q000737:chemistry / Q000235:genetics
chemical_list: D018952:Antigens, CD34; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D018800:Thy-1 Antigens; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D010649:Phenylalanine; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051997:ADP-ribosyl Cyclase 1; D014633:Valine