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Blood, 15 July 2007, Vol. 110, No. 2, pp. 686-694.
Prepublished online as a Blood First Edition Paper on March 26, 2007; DOI 10.1182/blood-2006-10-053181.
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Submitted October 19, 2006
Accepted March 13, 2007
Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential
Sridhar Vempati, Carola Reindl, Seshu Kumar Kaza, Ruth Kern, Theodora Malamoussi, Martin Dugas, Gudrun Mellert, Susanne Schnittger, Wolfgang Hiddemann, and Karsten Spiekermann*
CCG Leukemia, GSF-National Research Center for Environment and Health, Munich, Germany
Department of Medicine III, University of Munich-Grosshadem, Munich, Germany
Institute of Medical Informatics and Biomathematics, University of Munster, Munster, Germany
Laboratory for Leukemia Diagnostics, University of Munich- Grosshadern, Munich, Germany
Molecular Genetics, Munich Leukemia Laboratory, Munich, Germany
* Corresponding author; email: karsten.spiekermann{at}med.uni-muenchen.de.
FLT3-internal tandem duplications (FLT3-ITDs) are a heterogenous 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 (AA) with a median of 17 AA. The analysis of duplicated AAs showed that in the majority of patients, the duplications localize between AA 591 to 599 (YVDFREYEY). Arginine 595 (R595) within this region is duplicated in 77% of patients. Single duplication of R595 in FLT3 confered factor-independent growth to Ba/F3 cells and activated STAT5. Moreover, deletion or substitution of the duplicated R595 in two FLT3-ITD constructs as well as the deletion of wildtype-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.
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