title: The TEL/PDGFbetaR fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways.
abstract: The TEL/PDGFbetaR gene, which encodes a fusion protein containing the ETS-family member TEL fused to the protein-tyrosine kinase domain of the platelet-derived growth factor receptor-beta (PDGFbetaR), confers interleukin 3 (IL-3)-independent growth on Ba/F3 hematopoietic cells. TEL/PDGFbetaR mutants have been generated that contain tyrosine-to-phenylalanine (Tyr-->Phe) substitutions at phosphorylation sites present in the native PDGFbetaR to assess the role of these sites in cell transformation by TEL/PDGFbetaR. Similar to previous findings in a murine bone marrow transplantation model, full transformation of Ba/F3 cells to IL-3-independent survival and proliferation required the TEL/PDGFbetaR juxtamembrane and carboxy terminal phosphorylation sites. In contrast to previous reports concerning comparable mutants in the native PDGFbetaR, each of the TEL/PDGFbetaR mutants is fully active as a protein-tyrosine kinase. Expression of the TEL/PDGFbetaR fusion protein causes hyperphosphorylation and activation of signal transducer and activator of transcription (STAT5), and this activation of STAT5 requires the juxtamembrane Tyr579 and Tyr581 in the TEL/PDGFbetaR fusion. Hyperphosphosphorylation of phospholipase Cgamma (PLCgamma) and the p85 subunit of phosphatidylinositol 3-kinase (PI3K) requires the carboxy terminal tyrosine residues of TEL/PDGFbetaR. Thus, full transformation of Ba/F3 cells by TEL/PDGFbetaR requires engagement of PI3K and PLCgamma and activation of STAT5. Taken together with the growth properties of cells transformed by the TEL/PDGFbetaR variants, these findings indicate that a minimal combination of these signaling intermediates contributes to hematopoietic transformation by the wild-type TEL/PDGFbetaR fusion. (Blood. 2001;98:3390-3397)
authors.affiliation: Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Sternberg
authors.forename: M H
authors.initials: MH
authors.lastname: Tomasson
authors.forename: M
authors.initials: M
authors.lastname: Carroll
authors.forename: D P
authors.initials: DP
authors.lastname: Curley
authors.forename: G
authors.initials: G
authors.lastname: Barker
authors.forename: M
authors.initials: M
authors.lastname: Caprio
authors.forename: A
authors.initials: A
authors.lastname: Wilbanks
authors.forename: A
authors.initials: A
authors.lastname: Kazlauskas
authors.forename: D G
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology*; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008894:Milk Proteins; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D008894:Milk Proteins; D015514:Oncogene Proteins, Fusion; D050799:STAT5 Transcription Factor; C120888:TEL-PDGFRbeta fusion protein, human; D015534:Trans-Activators; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases