The t(5;12)(q33;p13) translocation associated with chronic myelomonocytic leukemia (CMML) generates a TEL/PDGFβR fusion gene. Here, we used a murine bone marrow transplant (BMT) assay to test the transforming properties of TEL/PDGFβR in vivo. TEL/PDGFβR, introduced into whole bone marrow by retroviral transduction, caused a rapidly fatal myeloproliferative disease that closely recapitulated human CMML. TEL/PDGFβR 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/PDGFβR fusion protein — including 8 tyrosine to phenylalanine substitutions at phosphorylated PDGFβR 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/PDGFβR is necessary and sufficient to induce a myeloproliferative disease in a murine BMT model, and PDGFβR residues Y579/581 are required for this phenotype.
Michael H. Tomasson, David W. Sternberg, Ifor R. Williams, Martin Carroll, Danielle Cain, Jon C. Aster, Robert L. Ilaria Jr., Richard A. Van Etten, D. Gary Gilliland
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