Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V 617 F mutation of Jak 2

We identified 13 new gene expression markers that were elevated and one marker, ANKRD15, that was down-regulated in patients with polycythemia vera (PV). These 14 markers, as well as the previously described PRV1 and NF-E2, exhibited the same gene expression alterations also in patients with exogenously activated granulocytes due to sepsis or granulocyte colony-stimulating factor (GCSF) treatment. The recently described V617F mutation in the Janus kinase 2 (JAK2) gene allows defining subclasses of patients with myeloproliferative disorders based on the JAK2 genotype. Patients with PV who were homozygous or heterozygous for JAK2-V617F exhibited higher levels of expression of the 13 new markers, PRV1, and NF-E2 than patients without JAK2-V617F, whereas ANKRD15 was down-regulated in these patients. Our results suggest that the alterations in expression of the markers studied are due to the activation of the Jak/signal transducer and activator of transcription (STAT) pathway through exogenous stimuli (sepsis or G-CSF treatment), or endogenously through the JAK2-V617F mutation. (Blood. 2005;106:3374-3376)

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

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

[3]  T. Maiwald,et al.  Gene expression profiling in polycythaemia vera: overexpression of transcription factor NF‐E2 , 2005, British journal of haematology.

[4]  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.

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

[6]  M. Cazzola,et al.  Clinical significance of neutrophil CD177 mRNA expression in Ph‐negative chronic myeloproliferative disorders , 2004, British journal of haematology.

[7]  Ulrich Schlecht,et al.  Expression profiling of mammalian male meiosis and gametogenesis identifies novel candidate genes for roles in the regulation of fertility. , 2003, Molecular biology of the cell.

[8]  H. Heimpel,et al.  Quantification of PRV-1 mRNA distinguishes polycythemia vera from secondary erythrocytosis. , 2003, Blood.

[9]  R. Kralovics,et al.  Comparison of molecular markers in a cohort of patients with chronic myeloproliferative disorders. , 2003, Blood.

[10]  C. Langford,et al.  Gene expression profiling in polycythemia vera using cDNA microarray technology. , 2003, Cancer research.

[11]  J. Jelinek,et al.  Discrimination of polycythemias and thrombocytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin. , 2003, Blood.

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

[13]  Ryoiti Kiyama,et al.  A Novel Ankyrin Repeat-containing Gene (Kank) Located at 9p24 Is a Growth Suppressor of Renal Cell Carcinoma* , 2002, The Journal of Biological Chemistry.

[14]  D. Aaronson,et al.  A Road Map for Those Who Don't Know JAK-STAT , 2002, Science.

[15]  A. Gurney,et al.  A Novel Type I Cytokine Receptor Is Expressed on Monocytes, Signals Proliferation, and Activates STAT-3 and STAT-5* , 2002, The Journal of Biological Chemistry.

[16]  R. Kralovics,et al.  Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. , 2002, Experimental hematology.

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

[18]  M. Lübbert,et al.  Cloning of PRV-1, a novel member of the uPAR receptor superfamily, which is overexpressed in polycythemia rubra vera. , 2000, Blood.

[19]  T. Pearson.  Evaluation of diagnostic criteria in polycythemia vera. , 2001, Seminars in hematology.

[20]  S. Murphy.  Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. , 1999, Seminars in hematology.