title: Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor.
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.
authors.affiliation: 3rd Medical Department, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Breitenbuecher
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Rebekka
authors.initials: R
authors.lastname: Grundler
authors.forename: Boyka
authors.initials: B
authors.lastname: Markova
authors.forename: Birgit
authors.initials: B
authors.lastname: Carius
authors.forename: Alexandra
authors.initials: A
authors.lastname: Brecht
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3