Source:http://linkedlifedata.com/resource/pubmed/id/18482053
Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
6
|
| pubmed:dateCreated |
2008-5-16
|
| pubmed:abstractText |
The somatic activating janus kinase 2 mutation (JAK2)(V617F) is detectable in most patients with polycythemia vera (PV). Here we report that CP-690,550 exerts greater antiproliferative and pro-apoptotic activity against cells harboring JAK2(V617F) compared with JAK2(WT). CP-690,550 treatment of murine factor-dependent cell Patersen-erythropoietin receptor (FDCP-EpoR) cells harboring human wild-type or V617F JAK2 resulted in inhibition of cell proliferation with a 50% inhibitory concentration (IC(50)) of 2.1 microM and 0.25 microM, respectively. Moreover, CP-690,550 induced a significant pro-apoptotic effect on murine FDCP-EpoR cells carrying JAK2(V617F), whereas a lesser effect was observed for cells carrying wild-type JAK2. This activity was coupled with inhibition of phosphorylation of the key JAK2(V617F)-dependent downstream signaling effectors signal transducer and activator of transcription (STAT)3, STAT5, and v-akt murine thymoma viral oncogene homolog (AKT). Furthermore, CP-690,550 treatment of ex-vivo-expanded erythroid progenitors from JAK2(V617F)-positive PV patients resulted in specific, antiproliferative (IC(50) = 0.2 microM) and pro-apoptotic activity. In contrast, expanded progenitors from healthy controls were less sensitive to CP-690,550 in proliferation (IC(50) > 1.0 microM), and apoptosis assays. The antiproliferative effect on expanded patient progenitors was paralleled by a decrease in JAK2(V617F) mutant allele frequency, particularly in a patient homozygous for JAK2(V617F). Flow cytometric analysis of expanded PV progenitor cells treated with CP-690,550 suggests a possible transition towards a pattern of erythroid differentiation resembling expanded cells from normal healthy controls.
|
| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Erythropoietin,
http://linkedlifedata.com/resource/pubmed/chemical/Janus Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrroles,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Erythropoietin,
http://linkedlifedata.com/resource/pubmed/chemical/STAT3 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Stat3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/tofacitinib
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jun
|
| pubmed:issn |
1349-7006
|
| pubmed:author | |
| pubmed:issnType |
Electronic
|
| pubmed:volume |
99
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1265-73
|
| pubmed:dateRevised |
2011-11-17
|
| pubmed:meshHeading |
pubmed-meshheading:18482053-Animals,
pubmed-meshheading:18482053-Apoptosis,
pubmed-meshheading:18482053-Blotting, Western,
pubmed-meshheading:18482053-Bone Marrow,
pubmed-meshheading:18482053-Cell Cycle,
pubmed-meshheading:18482053-Cell Nucleus,
pubmed-meshheading:18482053-Cell Proliferation,
pubmed-meshheading:18482053-Cells, Cultured,
pubmed-meshheading:18482053-Erythroid Precursor Cells,
pubmed-meshheading:18482053-Erythropoietin,
pubmed-meshheading:18482053-Flow Cytometry,
pubmed-meshheading:18482053-Humans,
pubmed-meshheading:18482053-Immunoprecipitation,
pubmed-meshheading:18482053-Janus Kinase 2,
pubmed-meshheading:18482053-Membrane Potential, Mitochondrial,
pubmed-meshheading:18482053-Mice,
pubmed-meshheading:18482053-Mutation,
pubmed-meshheading:18482053-Phosphorylation,
pubmed-meshheading:18482053-Polycythemia Vera,
pubmed-meshheading:18482053-Protein Kinase Inhibitors,
pubmed-meshheading:18482053-Protein Transport,
pubmed-meshheading:18482053-Pyrimidines,
pubmed-meshheading:18482053-Pyrroles,
pubmed-meshheading:18482053-Receptors, Erythropoietin,
pubmed-meshheading:18482053-STAT3 Transcription Factor,
pubmed-meshheading:18482053-Signal Transduction
|
| pubmed:year |
2008
|
| pubmed:articleTitle |
The JAK kinase inhibitor CP-690,550 suppresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation.
|
| pubmed:affiliation |
Department of Leukemia, The University of Texas, M D Anderson Cancer Center, Houston, TX 77030, USA.
|
| pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
|