title: Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice.
abstract: The 8p11 myeloproliferative syndrome (EMS), also referred to as stem cell leukemia/lymphoma, is a chronic myeloproliferative disorder that rapidly progresses into acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1 gene, resulting in constitutive activation of the tyrosine kinases in FGFR1. To date, no previous study has addressed the functional consequences of ectopic FGFR1 expression in the potentially most relevant cellular context, that of normal primary human hematopoietic cells. Herein, we report that expression of ZMYM2/FGFR1 (previously known as ZNF198/FGFR1) or BCR/FGFR1 in normal human CD34(+) cells from umbilical-cord blood leads to increased cellular proliferation and differentiation toward the erythroid lineage in vitro. In immunodeficient mice, expression of ZMYM2/FGFR1 or BCR/FGFR1 in human cells induces several features of human EMS, including expansion of several myeloid cell lineages and accumulation of blasts in bone marrow. Moreover, bone marrow fibrosis together with increased extramedullary hematopoiesis is observed. This study suggests that FGFR1 fusion oncogenes, by themselves, are capable of initiating an EMS-like disorder, and provides the first humanized model of a myeloproliferative disorder transforming into acute leukemia in mice. The established in vivo EMS model should provide a valuable tool for future studies of this disorder.
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden. helena.agerstam@med.lu.se
authors.forename: Helena
authors.initials: H
authors.lastname: Agerstam
authors.forename: Marcus
authors.initials: M
authors.lastname: Järås
authors.forename: Anna
authors.initials: A
authors.lastname: Andersson
authors.forename: Petra
authors.initials: P
authors.lastname: Johnels
authors.forename: Nils
authors.initials: N
authors.lastname: Hansen
authors.forename: Carin
authors.initials: C
authors.lastname: Lassen
authors.forename: Marianne
authors.initials: M
authors.lastname: Rissler
authors.forename: David
authors.initials: D
authors.lastname: Gisselsson
authors.forename: Tor
authors.initials: T
authors.lastname: Olofsson
authors.forename: Johan
authors.initials: J
authors.lastname: Richter
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Fan
authors.forename: Mats
authors.initials: M
authors.lastname: Ehinger
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
mesh_terms: D000818:Animals; D002898:Chromosomes, Human, Pair 8; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion; D055728:Primary Myelofibrosis; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C111777:ZMYM2 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051562:Proto-Oncogene Proteins c-bcr