Linked Life Data

19589925

Source:http://linkedlifedata.com/resource/pubmed/id/19589925

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2009-8-28
pubmed:abstractText
The JAK(V617F) mutation is responsible for the majority of breakpoint cluster region (BCR)/Abelson (ABL)-negative myeloproliferative disorders. Ongoing clinical trials of Janus kinase 2 (JAK2) inhibitors in myeloproliferative disorder patients use small molecules targeting both wild-type and mutated JAK2. To selectively target malignant cells, we developed JAK2(V617F)-specific small interfering RNAs or short hairpin RNAs. Expression of these RNAs in cell lines or CD34(+) cells from patients reduced JAK2(V617F)-driven autonomous cell proliferation. Mechanisms of inhibition involved selective JAK2(V617F) protein down-regulation, and consequently, decrease in signal transducer and activator of transcription 5 phosphorylation, cell-cycle progression, and cell survival. However, the addition of high concentrations of cytokines to cell lines or erythropoietin to patient cells greatly reduced growth inhibition. Similarly, the efficacy of a JAK2 small molecule inhibitor on cell line and patient cell proliferation dose dependently decreased with the addition of cytokines. Our results demonstrate that it is possible to specifically target JAK2(V617F) by RNA interference (RNAi) strategies. In addition, cytokines partially reverse the inhibition induced by both RNAi and small molecule approaches. This strongly suggests that patient cytokine levels in current JAK2 inhibitor clinical trials modulate the outcome of these therapies.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1528-0020
pubmed:author
pubmed:issnType
Electronic
pubmed:day
27
pubmed:volume
114
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1842-51
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Selective reduction of JAK2V617F-dependent cell growth by siRNA/shRNA and its reversal by cytokines.
pubmed:affiliation
Inserm, Unité 790, Institut Gustave Roussy, Villejuif, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't