Two Transforming C-RAF Germ-Line Mutations Identified in Patients with Therapy-Related Acute Myeloid Leukemia
| Autor: | Werner Emberger, Claudia Bodner, Armin Zebisch, Ali Delavar, Michael G. Schimek, Karin Hiden, Heinz Sill, Manickam Janakiraman, Philipp B. Staber, Christian Windpassinger, Jakob Troppmair, Holger W. Auner, Katja Fischereder, Werner Linkesch, Gerald Hoefler |
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| Rok vydání: | 2006 |
| Předmět: |
Adult
Proto-Oncogene Proteins B-raf MAPK/ERK pathway Cancer Research MAP Kinase Signaling System Molecular Sequence Data Apoptosis HL-60 Cells Therapy-Related Acute Myeloid Leukemia Biology medicine.disease_cause Mice Germline mutation Chlorocebus aethiops medicine Animals Humans Amino Acid Sequence c-Raf Phosphorylation Extracellular Signal-Regulated MAP Kinases Germ-Line Mutation Aged Mutation Base Sequence Gene Expression Regulation Leukemic Kinase Myeloid leukemia Neoplasms Second Primary medicine.disease Pedigree Proto-Oncogene Proteins c-raf Leukemia Cell Transformation Neoplastic Genes ras fms-Like Tyrosine Kinase 3 Oncology Leukemia Myeloid Acute Disease COS Cells NIH 3T3 Cells Cancer research Sequence Alignment |
| Zdroj: | Cancer Research. 66:3401-3408 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-05-0115 |
| Popis: | Mutations leading to activation of the RAF-mitogen-activated protein kinase/extracellular signal-regulated (ERK) kinase (MEK)-ERK pathway are key events in the pathogenesis of human malignancies. In a screen of 82 acute myeloid leukemia (AML) samples, 45 (55%) showed activated ERK and thus were further analyzed for mutations in B-RAF and C-RAF. Two C-RAF germ-line mutations, S427G and I448V, were identified in patients with therapy-related AML in the absence of alterations in RAS and FLT3. Both exchanges were located within the kinase domain of C-RAF. In vitro and in vivo kinase assays revealed significantly increased activity for S427GC-RAF but not for I448VC-RAF. The involvement of the S427G C-RAF mutation in constitutive activation of ERK was further confirmed through demonstration of activating phosphorylations on C-RAF, MEK, and ERK in neoplastic cells, but not in nonneoplastic cells. Transformation and survival assays showed oncogenic and antiapoptotic properties for both mutations. Screening healthy individuals revealed a |
| Databáze: | OpenAIRE |
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