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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2007-7-23
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pubmed:abstractText |
In acute myeloid leukemia (AML), mutational activation of the receptor tyrosine kinase (RTK) Flt3 is frequently involved in leukemic transformation. However, little is known about a possible role of highly expressed wild-type Flt3 in AML. The proto-oncogene c-Cbl is an important regulator of RTK signaling, acting through its ubiquitin ligase activity and as a platform for several signaling adaptor molecules. Here, we analyzed the role of c-Cbl in Flt3 signal transduction and myeloid transformation. C-Cbl physically interacted with Flt3 and was tyrosine phosphorylated in the presence of Flt3-ligand (FL). Overexpression of a dominant-negative form of c-Cbl (Cbl-70Z) inhibited FL-induced Flt3 ubiquitylation and internalization, indicating involvement of c-Cbl in Flt3 signaling. DNA sequencing of AML bone marrow revealed a case with a c-Cbl point mutation (Cbl-R420Q). Cbl-R420Q inhibited Flt3 internalization and ubiquitylation. Coexpression of Cbl-R420Q or Cbl-70Z with Flt3 induced cytokine-independent growth and survival of 32Dcl3 cells in the absence of FL. Also, the mutant Cbl proteins altered the amplitude and duration of Flt3-dependent signaling events. Our results indicate an important role of Cbl proteins in Flt3 signal modulation. Also, the data suggest a novel mechanism of leukemic transformation in AML by mutational inactivation of negative RTK regulators.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0006-4971
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pubmed:author |
pubmed-author:AugustBenjaminB,
pubmed-author:BandiSrinivasa RaoSR,
pubmed-author:BerdelWolfgang EWE,
pubmed-author:BrandtsChristianC,
pubmed-author:ChoudharyChunaramC,
pubmed-author:CrosettoNicolaN,
pubmed-author:DikicIvanI,
pubmed-author:DuysterJustusJ,
pubmed-author:GrundlerRebekkaR,
pubmed-author:KoschmiederSteffenS,
pubmed-author:Müller-TidowCarstenC,
pubmed-author:RensinghoffMarionM,
pubmed-author:SarginBülentB,
pubmed-author:SchmidtMirko H HMH,
pubmed-author:SchwäbleJoachimJ,
pubmed-author:ServeHubertH,
pubmed-author:ThiessenChristineC,
pubmed-author:TickenbrockLaraL
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
110
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1004-12
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:17446348-Animals,
pubmed-meshheading:17446348-Bone Marrow,
pubmed-meshheading:17446348-COS Cells,
pubmed-meshheading:17446348-Cell Survival,
pubmed-meshheading:17446348-Cell Transformation, Neoplastic,
pubmed-meshheading:17446348-Cercopithecus aethiops,
pubmed-meshheading:17446348-Gene Expression Regulation, Leukemic,
pubmed-meshheading:17446348-Genes, Dominant,
pubmed-meshheading:17446348-Humans,
pubmed-meshheading:17446348-Leukemia, Myeloid, Acute,
pubmed-meshheading:17446348-Mice,
pubmed-meshheading:17446348-Phosphorylation,
pubmed-meshheading:17446348-Point Mutation,
pubmed-meshheading:17446348-Protein Binding,
pubmed-meshheading:17446348-Protein Processing, Post-Translational,
pubmed-meshheading:17446348-Proto-Oncogene Proteins c-cbl,
pubmed-meshheading:17446348-Signal Transduction,
pubmed-meshheading:17446348-fms-Like Tyrosine Kinase 3
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pubmed:year |
2007
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pubmed:articleTitle |
Flt3-dependent transformation by inactivating c-Cbl mutations in AML.
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pubmed:affiliation |
Department of Medicine, Hematology and Oncology, and Interdisciplinary Center for Clinical Research, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48129 Münster, Germany.
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pubmed:publicationType |
Journal Article,
Clinical Trial,
Research Support, Non-U.S. Gov't
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