6533b854fe1ef96bd12ae047
RESEARCH PRODUCT
Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor
Boyka MarkovaSusanne SchnittgerBirgit CariusFrank BreitenbuecherFrank BreitenbuecherChristoph HuberThomas FischerRebekka GrundlerTorsten HaferlachAlexandra BrechtJustus Duystersubject
MutationImmunologyClone (cell biology)MedizinMyeloid leukemiaCell BiologyHematologyBiologymedicine.disease_causeBiochemistryMolecular biologyReceptor tyrosine kinasehemic and lymphatic diseasesTrk receptormedicinebiology.proteinPhosphorylationReceptorSTAT5description
Abstract In acute myeloid leukemia (AML), internal tandem duplications (ITDs) of the juxtamembrane (JM) of FLT3 have been shown to play a crucial role in driving proliferation and survival of the leukemic clone. Here, we report the identification of FLT3_ITD mutations located in non-JM domains of the FLT3-receptor. This novel type of FLT3_ITD mutation was found in 216 of 753 (28.7%) of unselected FLT3_ITD-positive AML cases. An FLT3 receptor harbouring a prototypic non-JM ITD (FLT3_ITD627E) mediated constitutive phosphorylation of FLT3 and of STAT5, suggesting that non-JM ITDs confer constitutive activation of the receptor. FLT3_ITD627E induced transformation of hematopoietic 32D cells and led to a lethal myeloproliferative disease in a syngeneic mouse model. Our results indicate that a significant proportion of activating FLT3_ITD mutations is not confined to the JM domain of FLT3. Further studies are warranted to define the biologic and clinical characteristics of non-JM ITDs.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2009-04-23 |