Fatal myeloproliferation, induced in mice by TEL/PDGF beta R expression, depends on PDGF beta R tyrosines 579/581

The t(5;12)(q33;p13) translocation associated with chronic myelomonocytic l eukemia (CMML) generates a TEL/PDGF beta R fusion gene. Here, we used a mur ine bone marrow transplant (BMT) assay to test the transforming properties of TEL/PDGF beta R in vivo. TEL/PDGF beta R, introduced into whole bone mar row by retroviral transduction, caused a rapidly fatal myeloproliferative d isease that closely recapitulated human CMML. TEL/PDGF beta R transplanted mice developed leukocytosis with Gr-1(+) granulocytes, splenomegaly, eviden ce of extramedullary hematopoiesis, and bone marrow fibrosis, but no lympho proliferative disease. We assayed mutant forms of the TEL/PDGF beta R fusio n protein - including 8 tyrosine to phenylalanine substitutions at phosphor ylated PDGF beta R sites to which various SH2 domain-containing signaling i ntermediates bind - for ability to transform hematopoietic cells. All of th e phenylalanine (F-) mutants tested conferred IL-3-independence to a cultur ed murine hematopoietic cell line, but, in the BMT assay, different P-mutan ts displayed distinct transforming properties. In transplanted animals, tyr osines 579/581 proved critical for the development of myeloproliferative ph enotype. F-mutants with these residues mutated showed no sign of myeloproli feration but instead developed T-cell lymphomas. In summary, TEL/PDGF beta R is necessary and sufficient to induce a myeloproliferative disease in a m urine BMT model, and PDGF beta R residues Y579/581 are required for this ph enotype.