Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts
| Autor: | KU Birkenkamp, Henny H. Lemmink, Wiebe Kruijer, M Geugien, Edo Vellenga |
|---|---|
| Přispěvatelé: | Groningen Biomolecular Sciences and Biotechnology, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL) |
| Rok vydání: | 2001 |
| Předmět: |
Cancer Research
Apoptosis RECEPTOR TYROSINE KINASE environment and public health Receptor tyrosine kinase chemistry.chemical_compound AML Gene Duplication hemic and lymphatic diseases STAT5 Transcription Factor HEMATOPOIETIC-CELLS Phosphorylation Flt3 STAT5 biology Kinase Autophosphorylation Myeloid leukemia Hematology COLONY-STIMULATING FACTOR Milk Proteins DNA-Binding Proteins TRANSCRIPTION FACTORS Oncology Leukemia Myeloid Acute Disease GROWTH Signal transduction FLT3 GENE JAK-STAT5 PATHWAY inorganic chemicals Blotting Western 32D CELLS Proto-Oncogene Proteins Humans ACUTE MYELOBLASTIC-LEUKEMIA Receptor Protein-Tyrosine Kinases Tyrosine phosphorylation constitutive activation INTERNAL TANDEM DUPLICATION enzymes and coenzymes (carbohydrates) fms-Like Tyrosine Kinase 3 chemistry Mutation Fms-Like Tyrosine Kinase 3 Trans-Activators biology.protein Cancer research bacteria |
| Zdroj: | Leukemia, 15(12), 1923-1931. Nature Publishing Group |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | In the present study, we examined the underlying mechanism, which causes the constitutive tyrosine phosphorylation of signal transducer and activator of transcription 5 (STAT5) in acute myeloid leukemia (AML) blasts. Constitutive STAT5 phosphorylation was observed in 18 of 26 (69%) patients with AML. The constitutive STAT5 phosphorylation was caused by different mechanisms. In the majority of the investigated cases (71% (12 of 17)) constitutive STAT5 phosphorylation was associated with autophosphorylation of the type III receptor tyrosine kinase Flt3. In 47% (eight of 17) of these cases autophosphorylation of Flt3 coincided with tandem duplications of the Flt3 gene, resulting in constitutive phosphorylation of the receptor, while 24% (four of 17) of the cases demonstrated STAT5 phosphorylation and Flt3 autophosphorylation without mutations. In addition, a subset of AML cases (29% (five of 17)) had no autophosphorylation of the Flt3 receptor, but demonstrated constitutive STAT5 phosphorylation, which was partly due to autocrine growth factor production. All AML cases with high STAT5 and Flt3 phosphorylation demonstrated, in general, a lower percentage of spontaneous apoptosis, compared to AML blasts with no spontaneous STAT5 phosphorylation. Addition of the receptor tyrosine III kinase inhibitor AG1296 strongly inhibited STAT5 phosphorylation and enhanced the percentage of apoptotic cells without modulating the Bcl-xl protein levels. These data indicate that in the majority of AML cases the constitutive STAT5 phosphorylation is caused by Flt3 phosphorylation mostly due to mutations in the receptors and associated with a low degree of spontaneous apoptosis. |
| Databáze: | OpenAIRE |
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