Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential

FLT3–internal tandem duplications (FLT3-ITDs) comprise a heterogeneous group of mutations in patients with acute leukemias that are prognostically important. To characterize the mechanism of transformation by FLT3-ITDs, we sequenced the juxtamembrane region (JM) of FLT3 from 284 patients with acute...

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Bibliographic Details
Published in:Blood 2007-07, Vol.110 (2), p.686-694
Main Authors: Vempati, Sridhar, Reindl, Carola, Kaza, Seshu Kumar, Kern, Ruth, Malamoussi, Theodora, Dugas, Martin, Mellert, Gudrun, Schnittger, Susanne, Hiddemann, Wolfgang, Spiekermann, Karsten
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Amino Acid Substitution
Arginine
Biological and medical sciences
Cell Transformation, Neoplastic - genetics
Female
fms-Like Tyrosine Kinase 3 - genetics
Gene Duplication
Hematologic and hematopoietic diseases
Humans
Leukemia - genetics
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Male
Medical sciences
Middle Aged
Mutagenesis
Sequence Deletion
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Summary:FLT3–internal tandem duplications (FLT3-ITDs) comprise a heterogeneous group of mutations in patients with acute leukemias that are prognostically important. To characterize the mechanism of transformation by FLT3-ITDs, we sequenced the juxtamembrane region (JM) of FLT3 from 284 patients with acute leukemias. The length of FLT3-ITDs varied from 2 to 42 amino acids (AAs) with a median of 17 AAs. The analysis of duplicated AAs showed that in the majority of patients, the duplications localize between AAs 591 to 599 (YVDFREYEY). Arginine 595 (R595) within this region is duplicated in 77% of patients. Single duplication of R595 in FLT3 conferred factor-independent growth to Ba/F3 cells and activated STAT5. Moreover, deletion or substitution of the duplicated R595 in 2 FLT3-ITD constructs as well as the deletion of wild-type R595 in FLT3-ITD substantially reduced the transforming potential and STAT5 activation, pointing to a critical role of the positive charge of R595 in stabilizing the active confirmation of FLT3-ITDs. Deletion of R595 in FLT3-WT nearly abrogated the ligand-dependent activation of FLT3-WT. Our data provide important insights into the molecular mechanism of transformation by FLT3-ITDs and show that duplication of R595 is important for the leukemic potential of FLT3-ITDs.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2006-10-053181