Characterization of the chronic myelomonocytic leukemia associated TEL-PDGFβR fusion protein

Abstract

The t(5;12) translocation, associated with chronic myelomonocytic leukemia, generates a novel gene encoding a protein, TEL-PDGFβR, composed of the 154 amino-terminal amino acids of the transcription factor TEL and the transmembrane and intracellular part of the PDGF β-receptor (PDGFβR). TEL also occurs as a tumor-associated fusion partner for the tyrosine kinases c-ABL, JAK2 and TRK-C. Previous studies have demonstrated growth promoting activity of TEL-PDGFβR and also indicated that the TEL moiety activates the tyrosine kinase of the PDGFβR through the formation of TEL-PDGFβR oligomers. We demonstrate that tyrosine phosphorylation of the fusion protein can be attenuated through overexpression of the TEL part of TEL-PDGFβR, suggesting a strategy for antagonizing the signaling of TEL-PDGFβR, and other TEL-fusion proteins containing tyrosine kinase domains. Comparison of BaF/3 cell lines expressing TEL-PDGFβR and ligand-stimulated PDGFβR revealed that only TEL-PDGFβR expression conferred IL-3-independent growth, suggesting differences in signaling capacity of the two proteins. Finally, tyrosine residues 17 and 27 in TEL-PDGFβR was identified as autophosphorylation sites in TEL-PDGFβR.