Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML.

2.50
Hdl Handle:
http://hdl.handle.net/10146/68853
Title:
Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML.
Authors:
Reindl, Carola; Bagrintseva, Ksenia; Vempati, Sridhar; Schnittger, Susanne; Ellwart, Joachim W.; Wenig, Katja; Hopfner, Karl-Peter; Hiddemann, Wolfgang; Spiekermann, Karsten
Abstract:
In acute myeloid leukemia (AML), two clusters of activating mutations are known in the FMS-like tyrosine kinase-3 (FLT3) gene: FLT3-internal tandem duplications (FLT3-ITDs) in the juxtamembrane (JM) domain in 20% to 25% of patients, and FLT3 point mutations in the tyrosine-kinase domain (FLT3-TKD) in 7% to 10% of patients, respectively. Here, we have characterized a new class of activating point mutations (PMs) that cluster in a 16-amino acid stretch of the juxtamembrane domain of FLT3 (FLT3-JM-PMs). Expression of 4 FLT3-JM-PMs in interleukin-3 (IL-3)-dependent Ba/F3 cells led to factor-independent growth, hyperresponsiveness to FLT3 ligand, and resistance to apoptotic cell death. FLT3-JM-PM receptors were autophosphorylated and showed a higher constitutive dimerization rate compared with the FLT3-wild-type (WT) receptor. As a molecular mechanism, we could show activation of STAT5 and up-regulation of Bcl-x(L) by all FLT3-JM-PMs. The FLT3 inhibitor PKC412 abrogated the factor-independent growth of FLT3-JM-PM-expressing cells. Compared with FLT3-ITD and FLT3-TKD mutants, the FLT3-JM-PMs showed a weaker transforming potential related to lower autophosphorylation of the receptor and its downstream target STAT5. Mapping of the FLT3-JM-PMs on the crystal structure of FLT3 showed that these mutations reduce the stability of the autoinhibitory JM domain, and provides a structural basis for the transforming capacity of this new class of gain-of-function mutations of FLT3.
Citation:
Blood 2006, 107 (9):3700-3707
Journal:
Blood
Issue Date:
1-May-2006
URI:
http://hdl.handle.net/10146/68853
DOI:
10.1182/blood-2005-06-2596
PubMed ID:
16410449
Additional Links:
http://bloodjournal.hematologylibrary.org/cgi/content/full/107/9/3700
Type:
Article
Language:
en
Description:
KEYWORDS - CLASSIFICATION: analogs & derivatives;Amino Acid Sequence;Animals;Apoptosis;Base Sequence;chemistry;Cell Line;DNA,Neoplasm;enzymology;Environment;Enzyme Activation;fms-Like Tyrosine Kinase 3;genetics;Germany;Humans;Interleukin-3;Leukemia;Leukemia,Myelocytic,Acute;metabolism;mechanisms of carcinogenesis;Mice;Models,Molecular;Molecular Sequence Data;Mutagenesis,Site-Directed;pharmacology;Phosphorylation;Point Mutation;Protein Structure,Tertiary;Proteins;Recombinant Proteins;Research;Staurosporine;STAT5 Transcription Factor;Tyrosine.
ISSN:
0006-4971
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
dc.contributor.authorReindl, Carola-
dc.contributor.authorBagrintseva, Ksenia-
dc.contributor.authorVempati, Sridhar-
dc.contributor.authorSchnittger, Susanne-
dc.contributor.authorEllwart, Joachim W.-
dc.contributor.authorWenig, Katja-
dc.contributor.authorHopfner, Karl-Peter-
dc.contributor.authorHiddemann, Wolfgang-
dc.contributor.authorSpiekermann, Karsten-
dc.date.accessioned2009-05-25T07:35:08Z-
dc.date.available2009-05-25T07:35:08Z-
dc.date.issued2006-05-01-
dc.identifier.citationBlood 2006, 107 (9):3700-3707en
dc.identifier.issn0006-4971-
dc.identifier.pmid16410449-
dc.identifier.doi10.1182/blood-2005-06-2596-
dc.identifier.urihttp://hdl.handle.net/10146/68853-
dc.descriptionKEYWORDS - CLASSIFICATION: analogs & derivatives;Amino Acid Sequence;Animals;Apoptosis;Base Sequence;chemistry;Cell Line;DNA,Neoplasm;enzymology;Environment;Enzyme Activation;fms-Like Tyrosine Kinase 3;genetics;Germany;Humans;Interleukin-3;Leukemia;Leukemia,Myelocytic,Acute;metabolism;mechanisms of carcinogenesis;Mice;Models,Molecular;Molecular Sequence Data;Mutagenesis,Site-Directed;pharmacology;Phosphorylation;Point Mutation;Protein Structure,Tertiary;Proteins;Recombinant Proteins;Research;Staurosporine;STAT5 Transcription Factor;Tyrosine.en
dc.description.abstractIn acute myeloid leukemia (AML), two clusters of activating mutations are known in the FMS-like tyrosine kinase-3 (FLT3) gene: FLT3-internal tandem duplications (FLT3-ITDs) in the juxtamembrane (JM) domain in 20% to 25% of patients, and FLT3 point mutations in the tyrosine-kinase domain (FLT3-TKD) in 7% to 10% of patients, respectively. Here, we have characterized a new class of activating point mutations (PMs) that cluster in a 16-amino acid stretch of the juxtamembrane domain of FLT3 (FLT3-JM-PMs). Expression of 4 FLT3-JM-PMs in interleukin-3 (IL-3)-dependent Ba/F3 cells led to factor-independent growth, hyperresponsiveness to FLT3 ligand, and resistance to apoptotic cell death. FLT3-JM-PM receptors were autophosphorylated and showed a higher constitutive dimerization rate compared with the FLT3-wild-type (WT) receptor. As a molecular mechanism, we could show activation of STAT5 and up-regulation of Bcl-x(L) by all FLT3-JM-PMs. The FLT3 inhibitor PKC412 abrogated the factor-independent growth of FLT3-JM-PM-expressing cells. Compared with FLT3-ITD and FLT3-TKD mutants, the FLT3-JM-PMs showed a weaker transforming potential related to lower autophosphorylation of the receptor and its downstream target STAT5. Mapping of the FLT3-JM-PMs on the crystal structure of FLT3 showed that these mutations reduce the stability of the autoinhibitory JM domain, and provides a structural basis for the transforming capacity of this new class of gain-of-function mutations of FLT3.en
dc.language.isoenen
dc.relation.urlhttp://bloodjournal.hematologylibrary.org/cgi/content/full/107/9/3700en
dc.subject.meshAmino Acid Sequence-
dc.subject.meshAnimals-
dc.subject.meshApoptosis-
dc.subject.meshBase Sequence-
dc.subject.meshCell Line-
dc.subject.meshDNA, Neoplasm-
dc.subject.meshEnzyme Activation-
dc.subject.meshHumans-
dc.subject.meshInterleukin-3-
dc.subject.meshLeukemia, Myeloid, Acute-
dc.subject.meshMice-
dc.subject.meshModels, Molecular-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshMutagenesis, Site-Directed-
dc.subject.meshPhosphorylation-
dc.subject.meshPoint Mutation-
dc.subject.meshProtein Structure, Tertiary-
dc.subject.meshRecombinant Proteins-
dc.subject.meshSTAT5 Transcription Factor-
dc.subject.meshStaurosporine-
dc.subject.meshTyrosine-
dc.subject.meshfms-Like Tyrosine Kinase 3-
dc.titlePoint mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML.en
dc.typeArticleen
dc.identifier.journalBlooden

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