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Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML.
- Source :
-
Blood [Blood] 2006 May 01; Vol. 107 (9), pp. 3700-7. Date of Electronic Publication: 2006 Jan 12. - Publication Year :
- 2006
-
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.
- Subjects :
- Amino Acid Sequence
Animals
Apoptosis
Base Sequence
Cell Line
DNA, Neoplasm genetics
Enzyme Activation genetics
Humans
In Vitro Techniques
Interleukin-3 pharmacology
Mice
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
Phosphorylation
Protein Structure, Tertiary
Recombinant Proteins chemistry
Recombinant Proteins genetics
Recombinant Proteins metabolism
STAT5 Transcription Factor metabolism
Staurosporine analogs & derivatives
Staurosporine pharmacology
Tyrosine chemistry
fms-Like Tyrosine Kinase 3 chemistry
fms-Like Tyrosine Kinase 3 metabolism
Leukemia, Myeloid, Acute enzymology
Leukemia, Myeloid, Acute genetics
Point Mutation
fms-Like Tyrosine Kinase 3 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 107
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 16410449
- Full Text :
- https://doi.org/10.1182/blood-2005-06-2596