0000000000608476

AUTHOR

Birgit Carius

showing 5 related works from this author

Mechanisms of Resistance to the FLT3-Tyrosine Kinase Inhibitor PKC412 in Patients with AML.

2004

Abstract The FLT3 receptor tyrosine kinase is expressed in 70-90% of cases of AML. Up to 35% of patients with AML show mutations in the JM-region or kinase domain of FLT3. These lead to autophosphorylation promoting ligand-independent cell proliferation and inhibition of apoptosis. Treatment with FLT3 tyrosine kinase inhibitors (TKI) is a promising tool in therapy of AML. Preliminary results investigating the FLT3-TKI PKC412 in patients with relapsed/refractory AML revealed that 11/15 patients (73%) with mutated FLT3 and 16/46 patients (35%) with WT FLT3 showed a >50% blast response in peripheral blood (Estey E et al. Blood.2003; 102:919a). Despite its remarkable efficacy in reducing…

biologymedicine.drug_classKinaseCell growthImmunologyAutophosphorylationClone (cell biology)Cell BiologyHematologyBiochemistryTyrosine-kinase inhibitorReceptor tyrosine kinasehemic and lymphatic diseasesImmunologymedicinebiology.proteinCancer researchPhosphorylationTyrosine kinaseBlood
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In BCR-ABL-positive cells, STAT-5 tyrosine-phosphorylation integrates signals induced by imatinib mesylate and Ara-C.

2003

In BCR-ABL-positive cells, the transcription factor STAT-5 is constitutively activated by tyrosine phosphorylation. STAT-5 activation results in upregulation of bcl-X(L) and increased resistance to induction of apoptosis. Here, we investigated the effects of imatinib mesylate and cytosine arabinoside (Ara-C) on STAT-5 tyrosine-phosphorylation, cellular proliferation and induction of apoptosis in cell lines and primary hematopoietic cells. Imatinib mesylate treatment strongly suppressed STAT-5 tyrosine-phosphorylation in K562 and primary CML blasts. In contrast to JAK-2 and PI-3-kinase inhibition, exposure of K562 cells to imatinib mesylate resulted in obvious suppression of proliferation. R…

Cancer ResearchProgrammed cell deathBlotting WesternFusion Proteins bcr-ablDown-RegulationAntineoplastic AgentsApoptosisBiologyPiperazineschemistry.chemical_compoundDownregulation and upregulationhemic and lymphatic diseasesLeukemia Myelogenous Chronic BCR-ABL PositivemedicineIn Situ Nick-End LabelingSTAT5 Transcription FactorHumansEnzyme InhibitorsPhosphorylationCell growthCytarabineImatinibTyrosine phosphorylationDrug SynergismHematologyDNAU937 CellsProtein-Tyrosine KinasesMilk ProteinsPrecipitin TestsDNA-Binding ProteinsImatinib mesylatePyrimidinesOncologychemistryApoptosisCaspasesBenzamidesCancer researchImatinib MesylateTrans-ActivatorsTyrosinePoly(ADP-ribose) PolymerasesK562 CellsCell Divisionmedicine.drugK562 cellsSignal TransductionLeukemia
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Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor

2009

Abstract In acute myeloid leukemia (AML), internal tandem duplications (ITDs) of the juxtamembrane (JM) of FLT3 have been shown to play a crucial role in driving proliferation and survival of the leukemic clone. Here, we report the identification of FLT3_ITD mutations located in non-JM domains of the FLT3-receptor. This novel type of FLT3_ITD mutation was found in 216 of 753 (28.7%) of unselected FLT3_ITD-positive AML cases. An FLT3 receptor harbouring a prototypic non-JM ITD (FLT3_ITD627E) mediated constitutive phosphorylation of FLT3 and of STAT5, suggesting that non-JM ITDs confer constitutive activation of the receptor. FLT3_ITD627E induced transformation of hematopoietic 32D cells and …

MutationImmunologyClone (cell biology)MedizinMyeloid leukemiaCell BiologyHematologyBiologymedicine.disease_causeBiochemistryMolecular biologyReceptor tyrosine kinasehemic and lymphatic diseasesTrk receptormedicinebiology.proteinPhosphorylationReceptorSTAT5
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The DNA-binding subunit p140 of replication factor C is upregulated in cycling cells and associates with G 1 phase cell cycle regulatory proteins

1999

The DNA-binding subunit of replication factor C (RFCp140) plays an important role in both DNA replication and DNA repair. The mechanisms regulating activation of RFCp140 thereby controlling replication and cellular proliferation are largely unknown. We analyzed protein expression of RFCp140 during cell cycle progression and investigated the association of RFCp140 with cell cycle regulatory proteins in cell lines of various tissue origin and in primary hematopoietic cells. Western and Northern blot analyses of RFCp140 from synchronized cells showed downregulation of RFCp140 when cells enter a G0-like quiescent state and upregulation of RFCp140 in cycling cells. Translocation from the cytopla…

CytoplasmSaccharomyces cerevisiae ProteinsT-LymphocytesCyclin ACell Cycle ProteinsEukaryotic DNA replicationCell LineMinor Histocompatibility AntigensDNA replication factor CDT1MiceReplication factor CControl of chromosome duplicationDrug DiscoveryAnimalsHumansReplication Protein CGenetics (clinical)Cell NucleusHomeodomain ProteinsbiologyG1 PhaseS-phase-promoting factor3T3 CellsCell cycleMolecular biologyUp-RegulationCell biologyDNA-Binding ProteinsRepressor ProteinsProto-Oncogene Proteins c-bcl-2biology.proteinMolecular MedicineOrigin recognition complexJournal of Molecular Medicine
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A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML

2009

Abstract Currently, FLT3 tyrosine kinase inhibitors (TKIs) are emerging as the most promising drug therapy to overcome the dismal prognosis of acute myelogenous leukemia (AML) patients harboring internal tandem duplications (ITDs) of FLT3. However, up-front drug resistance occurs in approximately 30% of patients, and molecular mechanisms of resistance are poorly understood. Here, we have uncovered a novel mechanism of primary resistance to FLT3 TKIs in AML: an FLT3 receptor harboring a nonjuxtamembrane ITD atypically integrating into the β-2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic myeloid cell leukemia 1 protein (MCL-1). Using RNA…

KinaseMitogen-Activated Protein Kinase 3ImmunologySignal transducing adaptor proteinCell BiologyHematologyBiologyBiochemistryProtein kinase domainhemic and lymphatic diseasesTrk receptorFms-Like Tyrosine Kinase 3Cancer researchSignal transductionTyrosine kinaseBlood
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