? ? The long-term objective of this research project is to define the molecular basis of polycythemia vera (PV). We previously identified unique molecular defects in thrombopoietin (TPO) receptor (Mpl) gene expression that were associated clinically with distinct myeloproliferative phenotypes. We have now identified a JAK2 gene mutation which was also intimately associated with myeloproliferative disease clinical phenotypes in a gene dosage-dependent manner. We have also observed that gene expression profiling of PV peripheral blood (pb) CD34+ cells not only permitted the diagnosis of PV but also identified heterogeneity amongst PV patients with respect to disease behavior. Importantly, PV patients with aggressive versus indolent disease as defined by gene expression profiling exhibited different combinations of JAK2 and Mpl genetic and epigenetic defects. Thus we hypothesize that PV is a polygenic disorder and that cumulative abnormalities of the JAK2 gene and Mpl are required to generate a PV. We hypothesize that these cumulative defects are responsible for the variability of myeloproliferative disease phenotypes. We also hypothesize that mutant JAK2 gene expression and function is integrally involved on the pathogenesis of PV through aberrant signal transduction and Mpl protein processing abnormalities. To test these hypotheses, we propose to define the effect of mutated JAK2 on intracellular signal transduction and Mpl expression and function, to define the relationship between mutated JAK2 and Mpl genetic and epigenetic alterations in PV patients with respect to disease phenotype and to determine whether PV clinical phenotypes as defined by PV blood and marrow CD34+ cell gene expression profiling and JAK2/Mpl genetic defects are recapitulated by xenotransplantation of these cells in NOD/SCID mice. (End of Abstract) ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082995-04
Application #
7467901
Study Section
Special Emphasis Panel (ZHL1-CSR-I (S2))
Program Officer
Di Fronzo, Nancy L
Project Start
2005-09-15
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$388,754
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Nischal, Sangeeta; Bhattacharyya, Sanchari; Christopeit, Maximilian et al. (2013) Methylome profiling reveals distinct alterations in phenotypic and mutational subgroups of myeloproliferative neoplasms. Cancer Res 73:1076-85
Stein, Brady L; Williams, Donna M; Rogers, Ophelia et al. (2011) Disease burden at the progenitor level is a feature of primary myelofibrosis: a multivariable analysis of 164 JAK2 V617F-positive myeloproliferative neoplasm patients. Exp Hematol 39:95-101
Stein, Brady L; Williams, Donna M; O'Keefe, Christine et al. (2011) Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes. Haematologica 96:1462-9
Stein, Brady L; Williams, Donna M; Wang, Nae-Yuh et al. (2010) Sex differences in the JAK2 V617F allele burden in chronic myeloproliferative disorders. Haematologica 95:1090-7
Laughlin, Todd S; Moliterno, Alison R; Stein, Brady L et al. (2010) Detection of exon 12 Mutations in the JAK2 gene: enhanced analytical sensitivity using clamped PCR and nucleotide sequencing. J Mol Diagn 12:278-82
Stein, Brady L; Moliterno, Alison R (2010) Primary myelofibrosis and the myeloproliferative neoplasms: the role of individual variation. JAMA 303:2513-8
Ye, Zhaohui; Zhan, Huichun; Mali, Prashant et al. (2009) Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 114:5473-80
Moliterno, Alison R; Williams, Donna M; Rogers, Ophelia et al. (2008) Phenotypic variability within the JAK2 V617F-positive MPD: roles of progenitor cell and neutrophil allele burdens. Exp Hematol 36:1480-6
Williams, Donna M; Kim, Ann H; Rogers, Ophelia et al. (2007) Phenotypic variations and new mutations in JAK2 V617F-negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis. Exp Hematol 35:1641-6

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