title: Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model.
abstract: Acute myeloid leukemia (AML) is a heterogeneous disease comprising a large number of subtypes defined by specific chromosome abnormalities. One such subtype carries the t(6;9)(p22;q34) chromosome rearrangement, which leads to expression of the DEK-NUP214 chimeric gene, and has a particularly poor outcome. To provide a better understanding of the molecular etiology of these relatively rare individual AML variants, it is necessary to generate in vivo models, which can also serve as a means to evaluate targeted therapies based on their specific genetic abnormalities. Here, we describe the development of a human cell AML, generated in CD34+ human hematopoietic progenitor cells xenografted into immunocompromised mice that express human myeloid cell growth factors. Within 6 months, these mice develop a human cell AML with phenotypic characteristics of the primary t(6;9) disease and a CD45+CD13+CD34+CD38+ immunophenotype. Gene expression studies show that members of the HOX family of genes (HOXA9, 10, B3, B4 and PBX3) are highly upregulated in the AML from this mouse model as well as from primary human t(6;9) AML. Gene expression analysis also identified several other significantly disregulated pathways involving KRAS, BRCA1 and ALK, for example. This is the first report of a humanized model of the DEK-NUP214 disease and provides a means to study the development and treatment of this particular subtype of AML.
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Qin
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Malek
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Cowell
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ren
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016867:Immunocompromised Host; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D005810:Multigene Family; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D014178:Translocation, Genetic
chemical_list: D018952:Antigens, CD34; D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D018398:Homeodomain Proteins; C085914:NUP214 protein, human; D028861:Nuclear Pore Complex Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D000075223:Poly-ADP-Ribose Binding Proteins; C088144:HoxA protein