Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML.
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Ellwart, Joachim W.
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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.
CitationBlood 2006, 107 (9):3700-3707
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.
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