title: Development of ZMYM2-FGFR1 driven AML in human CD34+ cells in immunocompromised mice.
abstract: Acute myelogenous leukemia (AML) has an overall poor survival rate and shows considerable molecular heterogeneity in its etiology. In the WHO classification there are >50 cytogenetic subgroups of AML, many showing highly specific chromosome translocations that lead to constitutive activation of individual kinases. In a rare stem cell leukemia/lymphoma syndrome, translocations involving 8p11 lead to constitutive activation of the fibroblast growth factor receptor 1 (FGFR1) kinase. This disorder shows myeloproliferative disease with almost invariable progresses to AML and conventional therapeutic strategies are largely unsuccessful. Because of the rare nature of this syndrome, models that faithfully recapitulate the human disease are needed to evaluate therapeutic strategies. The t(8;13)(p11;q12) chromosome translocation is most common rearrangement seen in this syndrome and creates a ZMYM2-FGFR1 chimeric kinase. To understand more about the molecular etiology of AML induced by this particular rearrangement, we have created a model human CD34+ cells transplanted into immunocompromized mice which develop myeloproliferative disease that progresses to AML with a long (>12 months) latency period. As in humans, these mice show hepatospenomegaly, hypercellular bone marrow and a CD45 + CD34 + CD13+ immunophenotype. Molecular studies demonstrate upregulation of genes such as KLF4 and FLT3 that promote stemness, and overexpression of MYC, which is associated with suppression of myeloid cell differentiation. This murine model, therefore, provides an opportunity to develop therapeutic strategies against the most common subtype within these FGFR1 driven neoplasms and study the molecular etiology in more depth.
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Ren
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qin
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA.|GRU Department of Pathology, Augusta, GA.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Savage
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, NM.
authors.forename: Tracy I
authors.initials: TI
authors.lastname: George
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA.
authors.forename: John K
authors.initials: JK
authors.lastname: Cowell
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015415:Biomarkers; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D016867:Immunocompromised Host; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D000090062:Kruppel-Like Factor 4; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010641:Phenotype; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; D015415:Biomarkers; D004268:DNA-Binding Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C111777:ZMYM2 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: 8p11 translocation; AML; FGFR1; mouse model; myeloproliferative disease