Fatal myeloproliferation, induced in mice by TEL/PDGFbetaR expression, depends on PDGFbetaR tyrosines 579/581.
The t(5;12)(q33;p13) translocation associated with chronic myelomonocytic leukemia (CMML) generates a TEL/PDGFbetaR fusion gene. Here, we used a murine bone marrow transplant (BMT) assay to test the transforming properties of TEL/PDGFbetaR in vivo. TEL/PDGFbetaR, introduced into whole bone marrow by retroviral transduction, caused a rapidly fatal myeloproliferative disease that closely recapitulated human CMML. TEL/PDGFbetaR transplanted mice developed leukocytosis with Gr-1(+) granulocytes, splenomegaly, evidence of extramedullary hematopoiesis, and bone marrow fibrosis, but no lymphoproliferative disease. We assayed mutant forms of the TEL/PDGFbetaR fusion protein - including 8 tyrosine to phenylalanine substitutions at phosphorylated PDGFbetaR sites to which various SH2 domain-containing signaling intermediates bind - for ability to transform hematopoietic cells. All of the phenylalanine (F-) mutants tested conferred IL-3-independence to a cultured murine hematopoietic cell line, but, in the BMT assay, different F-mutants displayed distinct transforming properties. In transplanted animals, tyrosines 579/581 proved critical for the development of myeloproliferative phenotype. F-mutants with these residues mutated showed no sign of myeloproliferation but instead developed T-cell lymphomas. In summary, TEL/PDGFbetaR is necessary and sufficient to induce a myeloproliferative disease in a murine BMT model, and PDGFbetaR residues Y579/581 are required for this phenotype.
Tomasson
M H
MH
Department of Medicine, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA.
Sternberg
D W
DW
Williams
I R
IR
Carroll
M
M
Cain
D
D
Aster
J C
JC
Ilaria
R L
RL
Van Etten
R A
RA
Gilliland
D G
DG
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015329:Gene Rearrangement, T-Lymphocyte; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D015479:Leukemia, Myelomonocytic, Acute / Q000209:etiology*; D016399:Lymphoma, T-Cell; D051379:Mice; D008807:Mice, Inbred BALB C; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013577:Syndrome; D016378:Tissue Transplantation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D016662:Virus Integration; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D017479:Receptors, Platelet-Derived Growth Factor; D012097:Repressor Proteins; D014157:Transcription Factors; D014443:Tyrosine; D000097764:ETS Translocation Variant 6 Protein; C120888:TEL-PDGFRbeta fusion protein, human