The Tel-PDGFR beta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice

Chronic myelomonocytic leukemia (CMML) is a pre-leukemic syndrome that disp lays both myelodysplastic and myeloproliferative features. The t(5;12) chro mosomal translocation, present in a subset of CMML patients with myeloproli feration fuses the amino terminal portion of the ets family member, Tel, wi th the transmembrane and tyrosine kinase domains of platelet-derived growth factor receptor beta (PDGFR beta) gene. To investigate the role of this fu sion protein in the pathogenesis of CMML, we expressed the Tel-PDGFR beta f usion cDNA in hematopoietic cells of transgenic mice under the control of t he human CD11a promoter. Transgenic founders and their offspring express th e transgene specifically in hematopoietic tissues and develop a myeloprolif erative syndrome characterized by: overproduction of mature neutrophils and megakaryocytes in the bone marrow; splenomegaly with effacement of splenic architecture by extramedullary hematopoiesis; an abnormal population of le ukocytes cc-expressing lymphoid and myeloid markers; and increased numbers of colonies in in vitro bone marrow CFU assays. All mice expressing the tra nsgene exhibited at least one of these features of dysregulated myelopoiesi s, and 20% progressed to a myeloid or lymphoid malignancy. This murine mode l of CMML parallels a myeloproliferative syndrome in humans and implicates the Tel-PDGFR beta fusion protein in its pathogenesis.