A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia
| Autor: | D. Gary Gilliland, Valerie Goss, Ting-Lei Gu, Roberto D. Polakiewicz, Lana Popova, Melanie G. Cornejo, Michael Heinrich, Brian J. Druker, Cynthia Reeves, Kimberly Lee, Jeffrey W. Tyner, Isao Miyoshi, Masanori Daibata, Denise K. Walters, Thomas Mercher, John Rush |
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| Rok vydání: | 2007 |
| Předmět: |
Myeloid
Oncogene Proteins Fusion Cell Survival Transplantation Heterologous Immunology Receptor Macrophage Colony-Stimulating Factor Biochemistry Translocation Genetic Receptor tyrosine kinase Cell Line Mice Acute megakaryoblastic leukemia Leukemia Megakaryoblastic Acute Cell Line Tumor medicine Animals Humans Cell Proliferation Neoplasia biology Cell growth Kinase RNA-Binding Proteins Myeloid leukemia Sequence Analysis DNA Cell Biology Hematology Protein-Tyrosine Kinases medicine.disease Molecular biology Fusion protein medicine.anatomical_structure biology.protein Chromosomes Human Pair 5 Chromosomes Human Pair 3 Tyrosine kinase Neoplasm Transplantation |
| Zdroj: | Blood. 110:323-333 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2006-10-052282 |
| Popis: | Activated tyrosine kinases have been frequently implicated in the pathogenesis of cancer, including acute myeloid leukemia (AML), and are validated targets for therapeutic intervention with small-molecule kinase inhibitors. To identify novel activated tyrosine kinases in AML, we used a discovery platform consisting of immunoaffinity profiling coupled to mass spectrometry that identifies large numbers of tyrosine-phosphorylated proteins, including active kinases. This method revealed the presence of an activated colony-stimulating factor 1 receptor (CSF1R) kinase in the acute megakaryoblastic leukemia (AMKL) cell line MKPL-1. Further studies using siRNA and a small-molecule inhibitor showed that CSF1R is essential for the growth and survival of MKPL-1 cells. DNA sequence analysis of cDNA generated by 5′RACE from CSF1R coding sequences identified a novel fusion of the RNA binding motif 6 (RBM6) gene to CSF1R gene generated presumably by a t(3;5)(p21;q33) translocation. Expression of the RBM6-CSF1R fusion protein conferred interleukin-3 (IL-3)–independent growth in BaF3 cells, and induces a myeloid proliferative disease (MPD) with features of megakaryoblastic leukemia in a murine transplant model. These findings identify a novel potential therapeutic target in leukemogenesis, and demonstrate the utility of phosphoproteomic strategies for discovery of tyrosine kinase alleles. |
| Databáze: | OpenAIRE |
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