Florian Perner1,2,3, Tina M Schnöder2,3, Thomas Fischer1,4, Florian H Heidel5,3,4. 1. Department of Hematology and Oncology, Center of Internal Medicine, Otto-von-Guericke University Medical Center, Magdeburg, Germany. 2. Internal medicine II, Hematology and Oncology, Friedrich-Schiller-University Medical Center, Jena, Germany. 3. Leibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany. 4. Collaborative Research Cluster 854, Medical Faculty, Otto-von-Guericke University Medical Center, Magdeburg, Germany. 5. Internal medicine II, Hematology and Oncology, Friedrich-Schiller-University Medical Center, Jena, Germany florian.h.heidel@gmail.com.
Abstract
BACKGROUND/AIM: The presence of FLT3-Internal tandem duplications (ITDs) in human acute myeloid leukemia (AML) is associated with a dismal prognosis. Altered cell-cycle activity has been reported in FLT3-ITD-positive AML; however, the mechanisms by which this oncogene influences cell-cycle activity remained so far elusive. MATERIALS AND METHODS: A phospho-kinomic screen was used to identify downstream effectors of FLT3-ITD. Validation and functional characterization was performed by western blotting, cell-cycle analysis and apoptosis assays. RESULTS: We identified aberrant phosphorylation of CDC25C-T48 in FLT3-ITD mutated cells. Forced expression of CDC25C affected cell-cycle progression but did not affect sensitivity to cellular stress. CONCLUSION: Depending on the oncogenic background, CDC25C may reveal protective or oncogenic functions. Our results identify CDC25C as a downstream target of the mutated tyrosine kinase FLT3-ITD affecting cell-cycle regulation in a model of AML. Copyright
BACKGROUND/AIM: The presence of FLT3-Internal tandem duplications (ITDs) in humanacute myeloid leukemia (AML) is associated with a dismal prognosis. Altered cell-cycle activity has been reported in FLT3-ITD-positive AML; however, the mechanisms by which this oncogene influences cell-cycle activity remained so far elusive. MATERIALS AND METHODS: A phospho-kinomic screen was used to identify downstream effectors of FLT3-ITD. Validation and functional characterization was performed by western blotting, cell-cycle analysis and apoptosis assays. RESULTS: We identified aberrant phosphorylation of CDC25C-T48 in FLT3-ITD mutated cells. Forced expression of CDC25C affected cell-cycle progression but did not affect sensitivity to cellular stress. CONCLUSION: Depending on the oncogenic background, CDC25C may reveal protective or oncogenic functions. Our results identify CDC25C as a downstream target of the mutated tyrosine kinase FLT3-ITD affecting cell-cycle regulation in a model of AML. Copyright
Authors: Mariette Labots; Johannes C Van der Mijn; Henk Dekker; Rita Ruijter; Thang V Pham; Hans J Van der Vliet; Jacobus J M Van der Hoeven; Gerrit A Meijer; Henk M W Verheul Journal: Oncologist Date: 2018-07-17