Fatal myeloproliferation, induced in mice by TEL/PDGFbetaR expression, depends on PDGFbetaR tyrosines 579/581

• Published in: The Journal of clinical investigation 2000-02, Vol.105 (4), p.423
• Main Authors: Tomasson, M H, Sternberg, D W, Williams, I R, Carroll, M, Cain, D, Aster, J C, Ilaria, Jr, R L, Van Etten, R A, Gilliland, D G
• Format: Article
• Language: English
• Subjects: Animals; Cell Transformation, Neoplastic; Clone Cells; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; ETS Translocation Variant 6 Protein; Gene Rearrangement, T-Lymphocyte; Gene Transfer Techniques; Genetic Vectors; Leukemia, Myelomonocytic, Acute - etiology; Lymphoma, T-Cell; Mice; Mice, Inbred BALB C; Oncogene Proteins, Fusion - metabolism; Proto-Oncogene Proteins c-ets; Receptors, Platelet-Derived Growth Factor - genetics; Receptors, Platelet-Derived Growth Factor - metabolism; Repressor Proteins; Retroviridae - genetics; Signal Transduction; Syndrome; Tissue Transplantation; Transcription Factors - genetics; Transcription Factors - metabolism; Tyrosine - metabolism; Virus Integration
• ISSN: 0021-9738

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.