[HTML][HTML] Fatal myeloproliferation, induced in mice by TEL/PDGFβR expression, depends on PDGFβR tyrosines 579/581

MH Tomasson, DW Sternberg… - The Journal of …, 2000 - Am Soc Clin Investig
MH Tomasson, DW Sternberg, IR Williams, M Carroll, D Cain, JC Aster, RL Ilaria…
The Journal of clinical investigation, 2000Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation