Linked Life Data

18670883

Source:http://linkedlifedata.com/resource/pubmed/id/18670883

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2008-8-11
pubmed:abstractText
High-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by the activation of the anti-apoptotic transcription factor NFkappaB, via the IKK complex. Here, we show that constitutive activation of the receptor tyrosine kinase Flt3 is responsible for IKK activation. Chemical inhibition or knockdown of Flt3 with small interfering RNAs reduced NFkappaB activation in MDS and AML cell lines, as well as in primary CD34(+) bone marrow cells from patients, causing apoptosis. Epistatic analysis involving the simultaneous inhibition of Flt3 and IKK suggested that both kinases act in the same anti-apoptotic pathway. An IKK2 mutant with a constitutive kinase activity and a plasma membrane-tethered mutant of NEMO that activates IKK1/2 prevented the cytocidal action of Flt3 inhibition. Flt3 phosphorylates IKK2 in vitro, and Flt3 inhibition reduced the phosphorylation of IKK2 in MDS or AML cell lines. IKK2 and Flt3 physically associated in MDS and AML cells, and Flt3 inhibition disrupted this interaction. Flt3 inhibition only killed CD34(+) bone marrow cells from high-risk MDS and AML patients, in correlation with blast numbers and NFkappaB activity, yet had no lethal effect on healthy CD34(+) cells or cells from low-risk MDS. These results suggest that Flt3 inhibitors might exert an anti-neoplastic effect in high-risk MDS and AML through inhibition of NFkappaB.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1573-675X
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
13
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1148-61
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Flt3 receptor inhibition reduces constitutive NFkappaB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia.
pubmed:affiliation
INSERM, U848, Institut Gustave Roussy, PR1, 38 rue Camille Desmoulins, 94805 Villejuif, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't