title: NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia.
abstract: The myelodysplastic syndromes (MDSs) are a group of clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis and dysplasia. A wide spectrum of genetic aberrations has been associated with MDS, including chromosomal translocations involving the NUP98 gene. Using a NUP98-HOXD13 fusion gene, we have developed a mouse model that faithfully recapitulates all of the key features of MDS, including peripheral blood cytopenias, bone marrow dysplasia, and apoptosis, and transformation to acute leukemia. The MDS that develops in NUP98-HOXD13 transgenic mice is uniformly fatal. Within 14 months, all of the mice died of either leukemic transformation or severe anemia and leucopenia as a result of progressive MDS. The NUP98-HOXD13 fusion gene inhibits megakaryocytic differentiation and increases apoptosis in the bone marrow, suggesting a mechanism leading to ineffective hematopoiesis in the presence of a hypercellular bone marrow. These mice provide an accurate preclinical model that can be used for the evaluation of MDS therapy and biology.
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20889, USA.
authors.forename: Ying-Wei
authors.initials: YW
authors.lastname: Lin
authors.forename: Christopher
authors.initials: C
authors.lastname: Slape
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Zhang
authors.forename: Peter D
authors.initials: PD
authors.lastname: Aplan
mesh_terms: D000208:Acute Disease; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000503:physiopathology*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D019683:Penetrance; D010641:Phenotype; D012720:Severity of Illness Index; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D002273:Carcinogens; C513184:HOXD13 protein, human; D018398:Homeodomain Proteins; C084118:Hoxd13 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; D014157:Transcription Factors; C093350:nuclear pore complex protein 98; D013755:Tetradecanoylphorbol Acetate