Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders.

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.

[1]  M. Cazzola,et al.  Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. , 2005, Blood.

[2]  D. Steensma,et al.  The JAK2V617F tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates , 2005 .

[3]  P. Guttorp,et al.  The kinetics of clonal dominance in myeloproliferative disorders. , 2005, Blood.

[4]  Qingshan Li,et al.  Identification of an Acquired JAK2 Mutation in Polycythemia Vera* , 2005, Journal of Biological Chemistry.

[5]  Stefan N Constantinescu,et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. , 2005, Nature.

[6]  K. Kaushansky On the molecular origins of the chronic myeloproliferative disorders: it all makes sense. , 2005, Hematology. American Society of Hematology. Education Program.

[7]  R. Hoffman,et al.  Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases. , 2005, Blood.

[8]  Mario Cazzola,et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. , 2005, The New England journal of medicine.

[9]  Sandra A. Moore,et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. , 2005, Cancer cell.

[10]  R. V. van Etten,et al.  JAKing up hematopoietic proliferation. , 2005, Cancer cell.

[11]  P. Campbell,et al.  Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders , 2005, The Lancet.

[12]  N. Mahmud,et al.  The constitutive mobilization of bone marrow-repopulating cells into the peripheral blood in idiopathic myelofibrosis. , 2005, Blood.

[13]  R. Mesa,et al.  Peripheral blood CD34 count in myelofibrosis with myeloid metaplasia: a prospective evaluation of prognostic value in 94 patients , 2005, British journal of haematology.

[14]  D. Steensma,et al.  The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates. , 2005, British journal of haematology.

[15]  J. D. van der Walt,et al.  European consensus on grading bone marrow fibrosis and assessment of cellularity. , 2005, Haematologica.

[16]  M. Cazzola,et al.  Gain of function, loss of control - a molecular basis for chronic myeloproliferative disorders. , 2005, Haematologica.

[17]  L. Luzzatto,et al.  CD157 is an important mediator of neutrophil adhesion and migration. , 2004, Blood.

[18]  J. Lévesque,et al.  Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. , 2003, The Journal of clinical investigation.

[19]  M. Cazzola,et al.  Clinical utility of the absolute number of circulating CD34-positive cells in patients with chronic myeloproliferative disorders. , 2003, Haematologica.

[20]  N. Harris,et al.  The World Health Organization (WHO) classification of the myeloid neoplasms. , 2002, Blood.

[21]  R. Taichman,et al.  G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4 , 2002, Nature Immunology.

[22]  T. Clackson,et al.  JAK2, complemented by a second signal from c‐kit or flt‐3, triggers extensive self‐renewal of primary multipotential hemopoietic cells , 2002, The EMBO journal.

[23]  G. Barosi,et al.  Diagnostic and clinical relevance of the number of circulating CD34(+) cells in myelofibrosis with myeloid metaplasia. , 2001, Blood.

[24]  T. Barbui,et al.  Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera , 2000 .

[25]  D Barnett,et al.  Cytofluorometric methods for assessing absolute numbers of cell subsets in blood. European Working Group on Clinical Cell Analysis. , 2000, Cytometry.

[26]  V. Diehl,et al.  Initial (prefibrotic) stages of idiopathic (primary) myelofibrosis (IMF) – a clinicopathological study , 1999, Leukemia.

[27]  M Marchetti,et al.  Neutrophil activation and hemostatic changes in healthy donors receiving granulocyte colony-stimulating factor. , 1999, Blood.

[28]  T. Barbui,et al.  Leucocyte alkaline phosphatase identifies terminally differentiated normal neutrophils and its lack in chronic myelogenous leukaemia is not dependent on p210 tyrosine kinase activity , 1999, British journal of haematology.

[29]  D. Sutherland,et al.  Single platform flow cytometric absolute CD34+ cell counts based on the ISHAGE guidelines. International Society of Hematotherapy and Graft Engineering. , 1998, Cytometry.

[30]  F Lacombe,et al.  Flow cytometry CD45 gating for immunophenotyping of acute myeloid leukemia , 1997, Leukemia.

[31]  Gregory T Stelzer,et al.  U.S.-Canadian Consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry: standardization and validation of laboratory procedures. , 1997, Cytometry.

[32]  T. Barbui,et al.  Flow cytometry of leucocyte alkaline phosphatase in normal and pathologic leucocytes , 1997, British journal of haematology.

[33]  P. Morel,et al.  Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. , 1996, Blood.

[34]  H. Sengeløv,et al.  Stimulus-dependent secretion of plasma proteins from human neutrophils. , 1992, The Journal of clinical investigation.

[35]  W. Dameshek Editorial: Some Speculations on the Myeloproliferative Syndromes , 1951 .

[36]  W. Dameshek Some speculations on the myeloproliferative syndromes. , 1951, Blood.