A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia

Blood. 2007 Jul 1;110(1):323-33. doi: 10.1182/blood-2006-10-052282. Epub 2007 Mar 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Chromosomes, Human, Pair 3
  • Chromosomes, Human, Pair 5
  • Humans
  • Leukemia, Megakaryoblastic, Acute / etiology
  • Leukemia, Megakaryoblastic, Acute / genetics*
  • Mice
  • Neoplasm Transplantation
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / isolation & purification
  • Oncogene Proteins, Fusion / physiology*
  • Protein-Tyrosine Kinases / isolation & purification
  • RNA-Binding Proteins / genetics*
  • Receptor, Macrophage Colony-Stimulating Factor / genetics*
  • Receptor, Macrophage Colony-Stimulating Factor / isolation & purification
  • Sequence Analysis, DNA
  • Translocation, Genetic
  • Transplantation, Heterologous


  • Oncogene Proteins, Fusion
  • RBM6 protein, human
  • RNA-Binding Proteins
  • Protein-Tyrosine Kinases
  • Receptor, Macrophage Colony-Stimulating Factor