title: Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders.
abstract: We studied the relationship between granulocyte JAK2 (V617F) mutation status, circulating CD34(+) cells, and granulocyte activation in myeloproliferative disorders. Quantitative allele-specific polymerase chain reaction (PCR) showed significant differences between various disorders with respect to either the proportion of positive patients (53%-100%) or that of mutant alleles, which overall ranged from 1% to 100%. In polycythemia vera, JAK2 (V617F) was detected in 23 of 25 subjects at diagnosis and in 16 of 16 patients whose disease had evolved into myelofibrosis; median percentages of mutant alleles in these subgroups were significantly different (32% versus 95%, P < .001). Circulating CD34(+) cell counts were variably elevated and associated with disease category and JAK2 (V617F) mutation status. Most patients had granulocyte activation patterns similar to those induced by administration of granulocyte colony-stimulating factor. A JAK2 (V617F) gene dosage effect on both CD34(+) cell counts and granulocyte activation was clearly demonstrated in polycythemia vera, where abnormal patterns were mainly found in patients carrying more than 50% mutant alleles. These observations suggest that JAK2 (V617F) may constitutively activate granulocytes and by this means mobilize CD34(+) cells. This exemplifies a novel paradigm in which a somatic gain-of-function mutation is initially responsible for clonal expansion of hematopoietic cells and later for their abnormal trafficking via an activated cell progeny.
authors.affiliation: Department of Hematology, IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.forename: Matteo G
authors.initials: MG
authors.lastname: Della Porta
authors.forename: Emanuela
authors.initials: E
authors.lastname: Boveri
authors.forename: Cristiana
authors.initials: C
authors.lastname: Pascutto
authors.forename: Laura
authors.initials: L
authors.lastname: Vanelli
authors.forename: Luca
authors.initials: L
authors.lastname: Arcaini
authors.forename: Sara
authors.initials: S
authors.lastname: Burcheri
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.forename: Mario
authors.initials: M
authors.lastname: Lazzarino
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D001483:Base Sequence; D016022:Case-Control Studies; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D006098:Granulocytes / Q000201:enzymology* / Q000276:immunology*; D006801:Humans; D053614:Janus Kinase 2; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000097:blood* / Q000235:genetics* / Q000276:immunology; D011087:Polycythemia Vera / Q000097:blood / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2