Characterization of the chronic myelomonocytic leukemia associated TEL-PDGF beta R fusion protein

The t(5;12) translocation, associated with chronic myelomonocytic leukemia, generates a novel gene encoding a protein, TEL-PDGF beta R, composed of th e 154 amino-terminal amino acids of the transcription factor TEL and the tr ansmembrane and intracellular part of the PDGF beta-receptor (PDGF beta R). TEL also occurs as a tumor-associated fusion partner for the tyrosine kina ses c-ABL, JAK2 and TRK-C. Previous studies have demonstrated growth promot ing activity of TEL-PDGF beta R and also indicated that the TEL moiety acti vates the tyrosine kinase of the PDGF beta R through the formation of TEL-P DGF beta R oligomers. We demonstrate that tyrosine phosphorylation of the f usion protein can be attenuated through overexpression of the TEL part of T EL-PDGF beta R, suggesting a strategy for antagonizing the signaling of TEL -PDGF beta R, and other TEL-fusion proteins containing tyrosine kinase doma ins. Comparison of BaF/3 cell lines expressing TEL-PDGF beta R and ligand-s timulated PDGF beta R revealed that only TEL-PDGF beta R expression conferr ed IL-3-independent growth, suggesting differences in signaling capacity of the two proteins. Finally, tyrosine residues 17 and 27 in TEL-PDGF beta R was identified as autophosphorylation sites in TEL-PDGF beta R.