title: The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice.
abstract: Chronic myelomonocytic leukemia (CMML) is a pre-leukemic syndrome that displays both myelodysplastic and myeloproliferative features. The t(5;12) chromosomal translocation, present in a subset of CMML patients with myeloproliferation fuses the amino terminal portion of the ets family member, Tel, with the transmembrane and tyrosine kinase domains of platelet-derived growth factor receptor beta (PDGFRbeta) gene. To investigate the role of this fusion protein in the pathogenesis of CMML, we expressed the Tel-PDGFRbeta fusion cDNA in hematopoietic cells of transgenic mice under the control of the human CD11a promoter. Transgenic founders and their offspring express the transgene specifically in hematopoietic tissues and develop a myeloproliferative 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 leukocytes co-expressing lymphoid and myeloid markers; and increased numbers of colonies in in vitro bone marrow CFU assays. All mice expressing the transgene exhibited at least one of these features of dysregulated myelopoiesis, and 20% progressed to a myeloid or lymphoid malignancy. This murine model of CMML parallels a myeloproliferative syndrome in humans and implicates the Tel-PDGFRbeta fusion protein in its pathogenesis.
authors.affiliation: Medical Research Service, VA Puget Sound Health Care System, Seattle, WA 98108, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Ritchie
authors.forename: A A
authors.initials: AA
authors.lastname: Aprikyan
authors.forename: D F
authors.initials: DF
authors.lastname: Bowen-Pope
authors.forename: C J
authors.initials: CJ
authors.lastname: Norby-Slycord
authors.forename: S
authors.initials: S
authors.lastname: Conyers
authors.forename: S
authors.initials: S
authors.lastname: Bartelmez
authors.forename: E H
authors.initials: EH
authors.lastname: Sitnicka
authors.forename: D D
authors.initials: DD
authors.lastname: Hickstein
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D020797:Receptor, Platelet-Derived Growth Factor beta; D012097:Repressor Proteins; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein