Journal article
The TEL/PDGFβR fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways
Blood, Vol.98(12), pp.3390-3397
12/01/2001
DOI: 10.1182/blood.V98.12.3390
PMID: 11719379
Abstract
AbstractThe TEL/PDGFβR 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-β (PDGFβR), confers interleukin 3 (IL-3)–independent growth on Ba/F3 hematopoietic cells. TEL/PDGFβR mutants have been generated that contain tyrosine-to-phenylalanine (Tyr→Phe) substitutions at phosphorylation sites present in the native PDGFβR to assess the role of these sites in cell transformation by TEL/PDGFβR. 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/PDGFβR juxtamembrane and carboxy terminal phosphorylation sites. In contrast to previous reports concerning comparable mutants in the native PDGFβR, each of the TEL/PDGFβR mutants is fully active as a protein-tyrosine kinase. Expression of the TEL/PDGFβR 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/PDGFβR fusion. Hyperphosphosphorylation of phospholipase Cγ (PLCγ) and the p85 subunit of phosphatidylinositol 3-kinase (PI3K) requires the carboxy terminal tyrosine residues of TEL/PDGFβR. Thus, full transformation of Ba/F3 cells by TEL/PDGFβR requires engagement of PI3K and PLCγ and activation of STAT5. Taken together with the growth properties of cells transformed by the TEL/PDGFβR variants, these findings indicate that a minimal combination of these signaling intermediates contributes to hematopoietic transformation by the wild-type TEL/PDGFβR fusion.
Details
- Title: Subtitle
- The TEL/PDGFβR fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways
- Creators
- David W Sternberg - From the Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MAMichael H Tomasson - From the Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MAMartin Carroll - From the Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MADavid P Curley - From the Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MAGeorge Barker - From the Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MAMichael Caprio - From the Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MAAlyson Wilbanks - From the Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MAAndrius Kazlauskas - From the Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MAD. Gary Gilliland - From the Howard Hughes Medical Institute, Harvard Medical School, Schepens Eye Research Institute, and Brigham and Women's Hospital, Boston, MA
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.98(12), pp.3390-3397
- DOI
- 10.1182/blood.V98.12.3390
- PMID
- 11719379
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 12/01/2001
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094485802771
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