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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3700-3707.
Prepublished online as a Blood First Edition Paper on January 12, 2006; DOI 10.1182/blood-2005-06-2596.
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NEOPLASIA
Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML
Carola Reindl,
Ksenia Bagrintseva,
Sridhar Vempati,
Susanne Schnittger,
Joachim W. Ellwart,
Katja Wenig,
Karl-Peter Hopfner,
Wolfgang Hiddemann, and
Karsten Spiekermann
From the Department of Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany; Clinical Cooperative Group "Leukemia" and Institute of Molecular Immunology, GSF-National Research Center for Environment and Health, Munich, Germany; and Gene Center and Department of Chemistry and Biochemistry, University of Munich, Germany.
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.
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