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Vempati, S. ; Reindl, C. ; Wolf, U. ; Kern, R. ; Petropoulos, K. ; Naidu, V.M. ; Buske, C. ; Hiddemann, W. ; Kohl, T.M. ; Spiekermann, K.

Transformation by oncogenic mutants and ligand-dependent activation of FLT3 wild-type requires the tyrosine residues 589 and 591.

Clin. Cancer Res. 14, 4437-4445 (2008)
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Mutations in the receptor tyrosine kinase FLT3 are found in up to 30% of acute myelogenous leukemia patients and are associated with an inferior prognosis. In this study, we characterized critical tyrosine residues responsible for the transforming potential of active FLT3-receptor mutants and ligand-dependent activation of FLT3-WT. EXPERIMENTAL DESIGN: We performed a detailed structure-function analysis of putative autophosphorylation tyrosine residues in the FLT3-D835Y tyrosine kinase domain (TKD) mutant. All tyrosine residues in the juxtamembrane domain (Y566, Y572, Y589, Y591, Y597, and Y599), interkinase domain (Y726 and Y768), and COOH-terminal domain (Y955 and Y969) of the FLT3-D835Y construct were successively mutated to phenylalanine and the transforming activity of these mutants was analyzed in interleukin-3-dependent Ba/F3 cells. Tyrosine residues critical for the transforming potential of FLT3-D835Y were also analyzed in FLT3 internal tandem duplication mutants (FLT3-ITD)and the FLT3 wild-type (FLT3-WT) receptor. RESULT: The substitution of the tyrosine residues by phenylalanine in the juxtamembrane, interkinase, and COOH-terminal domains resulted in a complete loss of the transforming potential of FLT3-D835Y-expressing cells which can be attributed to a significant reduction of signal tranducer and activator of transcription 5 (STAT5) phosphorylation at the molecular level. Reintroduction of single tyrosine residues revealed the critical role of Y589 and Y591 in reconstituting interleukin-3-independent growth of FLT3-TKD-expressing cells. Combined mutation of Y589 and Y591 to phenylalanine also abrogated ligand-dependent proliferation of FLT3-WT and the transforming potential of FLT3-ITD-with a subsequent abrogation of STAT5 phosphorylation. CONCLUSION: We identified two tyrosine residues, Y589 and Y591, in the juxtamembrane domain that are critical for the ligand-dependent activation of FLT3-WT and the transforming potential of oncogenic FLT3 mutants.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter acute myeloid-leukemia; internal tandem duplication; acute myelogenous leukemia; tyrosine kinase inhibitor; src family kinases; stem-cell factor; autophosphorylation sites; constitutive activation; transcription proteins; juxtamembrane domain
Sprache englisch
Veröffentlichungsjahr 2008
HGF-Berichtsjahr 2008
ISSN (print) / ISBN 1078-0432
e-ISSN 1557-3265
Zeitschrift Clinical Cancer Research
Quellenangaben Band: 14, Heft: 14, Seiten: 4437-4445 Artikelnummer: , Supplement: ,
Verlag American Association for Cancer Research (AACR)
Begutachtungsstatus Peer reviewed
Institut(e) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-521000-001
DOI 10.1158/1078-0432.CCR-07-1873
Scopus ID 51649125545
Erfassungsdatum 2008-12-15
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