Pim kinases phosphorylate Chk1 and regulate its functions in acute myeloid leukemia
| Autor: | Christian Recher, Christine Dozier, L L Yuan, Alexa S. Green, Stéphane Manenti, F Grimal, Christine Didier, V Mansat-De Mas, Jerome Tamburini, Sarah Bertoli |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Myeloid Intracellular Space PIM1 Biology environment and public health Histone H3 Proto-Oncogene Proteins c-pim-1 Cell Line Tumor Gene Duplication hemic and lymphatic diseases Serine medicine Humans Phosphorylation Protein kinase B Myeloid leukemia Hematology Cell cycle Leukemia Myeloid Acute Protein Transport enzymes and coenzymes (carbohydrates) medicine.anatomical_structure fms-Like Tyrosine Kinase 3 Oncology Checkpoint Kinase 1 embryonic structures Cancer research Ectopic expression biological phenomena cell phenomena and immunity Protein Kinases Signal Transduction |
| Zdroj: | Leukemia. 28:293-301 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2013.168 |
| Popis: | Phosphorylation by Akt on Ser 280 was reported to induce cytoplasmic retention and inactivation of CHK1 with consequent genetic instability in PTEN-/- cells. In acute myeloid leukemia cells carrying the FLT3-internal tandem duplication (ITD) mutation, we observed high rates of FLT3-ITD-dependent CHK1 Ser 280 phosphorylation. Pharmacological inhibition and RNA interference identified Pim1/2, not Akt, as effectors of this phosphorylation. Pim1 catalyzed Ser 280 phosphorylation in vitro and ectopic expression of Pim1/2-induced CHK1 phosphorylation. Ser 280 phosphorylation did not modify CHK1 localization, but facilitated its cell cycle and resistance functions in leukemic cells. FLT3, PIM or CHK1 inhibitors synergized with DNA-damaging agents to induce apoptosis, allowing cells to bypass the etoposide-induced G2/M arrest. Consistently, etoposide-induced CHK1-dependent phosphorylations of CDC25C on Ser 216 and histone H3 on Thr11 were decreased upon FLT3 inhibition. Accordingly, ectopic expression of CHK1 improved the resistance of FLT3-ITD cells and maintained histone H3 phosphorylation in response to DNA damage, whereas expression of unphosphorylated Ser 280Ala mutant did not. Finally, FLT3- and Pim-dependent phosphorylation of CHK1 on Ser 280 was confirmed in primary blasts from patients. These results identify a new pathway involved in the resistance of FLT3-ITD leukemic cells to genotoxic agents, and they constitute the first report of CHK1 Ser 280 regulation in myeloid malignancies. |
| Databáze: | OpenAIRE |
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