BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor–induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3
| Autor: | Andreas Villunger, Maria Kraft, Verena Labi, Amanda Nordigården, Eric Lam, Pernilla Eliasson, Jan-Ingvar Jönsson |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Apoptosis
Biochemistry Tyrosine-kinase inhibitor Mice Phosphatidylinositol 3-Kinases Transduction Genetic hemic and lymphatic diseases Puma Cytotoxic T cell RNA Small Interfering Oligonucleotide Array Sequence Analysis Bcl-2-Like Protein 11 biology Reverse Transcriptase Polymerase Chain Reaction Forkhead Box Protein O3 Forkhead Transcription Factors hemic and immune systems Hematology Protein-Tyrosine Kinases Tyrphostins Leukemia Myeloid Acute embryonic structures biological phenomena cell phenomena and immunity Stem cell Signal transduction Signal Transduction medicine.drug_class Blotting Western Immunology Article Cell Line Tumor Proto-Oncogene Proteins medicine Animals Humans Immunoprecipitation Progenitor cell Protein Kinase Inhibitors Membrane Proteins Cell Biology Hematopoietic Stem Cells Staurosporine biology.organism_classification fms-Like Tyrosine Kinase 3 Trk receptor Mutation Fms-Like Tyrosine Kinase 3 Cancer research Apoptosis Regulatory Proteins Proto-Oncogene Proteins c-akt |
| Zdroj: | Blood. 113:2302-2311 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2008-07-167023 |
| Popis: | Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD–mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapototic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras–mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition. |
| Databáze: | OpenAIRE |
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