TY - JOUR
T1 - The TEL/PDGFβR fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways
AU - Sternberg, David W.
AU - Tomasson, Michael H.
AU - Carroll, Martin
AU - Curley, David P.
AU - Barker, George
AU - Caprio, Michael
AU - Wilbanks, Alyson
AU - Kazlauskas, Andrius
AU - Gary Gilliland, D.
PY - 2001/12/1
Y1 - 2001/12/1
N2 - The 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.
AB - The 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.
UR - http://www.scopus.com/inward/record.url?scp=0035542766&partnerID=8YFLogxK
U2 - 10.1182/blood.V98.12.3390
DO - 10.1182/blood.V98.12.3390
M3 - Article
C2 - 11719379
AN - SCOPUS:0035542766
SN - 0006-4971
VL - 98
SP - 3390
EP - 3397
JO - Blood
JF - Blood
IS - 12
ER -