The driver of malignancy in KG-1a leukemic cells, FGFR1OP2-FGFR1, encodes an HSP90 addicted oncoprotein

Cell Signal. 2011 Nov;23(11):1758-66. doi: 10.1016/j.cellsig.2011.06.010. Epub 2011 Jun 30.


The KG-1a cell line is developed from a human stem cell myeloproliferative neoplasm as the result of intragenic disruption and a chromosomal translocation of the FGFR1 gene and the FGFR1OP2 gene encoding a protein of unknown function called FOP2 (FGFR1 Oncogene Partner 2). The resulting fusion protein FOP2-FGFR1 is soluble and has constitutive tyrosine kinase activity. Since the heat shock protein HSP90 and its co-chaperone CDC37 have been shown to stabilize many oncogenic proteins, we investigated the requirement for HSP90 or HSP90-CDC37 assistance to maintain the stability or activity of FOP2-FGFR1 expressed in KG-1a cells. We found that HSP90-CDC37 forms a permanent complex with FOP2-FGFR1. This results in protection against degradation of FOP2-FGFR1 and holds the oncoprotein in a permanently active conformation. Inhibition of HSP90 or depletion of CDC37 or heat shock factor 1 (HSF1) reduced the expression level of FOP2-FGFR1 and was sufficient to block the oncoprotein induced proliferation of KG-1a cells. We conclude that the driver of malignancy in KG-1a leukemic cells, FOP2-FGFR1, is an HSP90 addicted oncoprotein. This provides a rationale for the therapeutic use of HSP90 inhibitors in myeloid leukemias that contain FGFR fusion proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Chaperonins / genetics
  • Chaperonins / metabolism*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Immunoprecipitation
  • Leukemia, Myeloid / genetics
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Conformation
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Signal Transduction / genetics*
  • Translocation, Genetic


  • CDC37 protein, human
  • Cell Cycle Proteins
  • FOP-FGFR1 fusion protein, human
  • HSP90 Heat-Shock Proteins
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Receptors, Fibroblast Growth Factor
  • Receptor, Fibroblast Growth Factor, Type 1
  • Chaperonins