title: Hoxa9 collaborates with E2A-PBX1 in mouse B cell leukemia in association with Flt3 activation and decrease of B cell gene expression.
abstract: BACKGROUND
  The fusion protein E2A-PBX1 induces pediatric B cell leukemia in human. Previously, we reported oncogenic interactions between homeobox (Hox) genes and E2A-PBX1 in murine T cell leukemia. A proviral insertional mutagenesis screen with our E2A-PBX1 B cell leukemia mouse model identified Hoxa genes as potential collaborators to E2A-PBX1. Here we studied whether Hoxa9 could enhance E2A-PBX1 leukemogenesis.
  
  
  RESULTS
  We show that Hoxa9 confers a proliferative advantage to E2A-PBX1 B cells. Transplantation experiments with E2A-PBX1 transgenic B cells overexpressing Hoxa9 isolated from bone marrow chimeras showed that Hoxa9 accelerates the generation of E2A-PBX1 B cell leukemia, but Hoxa9 is unable to transform B cells alone. Quantitative-reverse transcriptase polymerase chain reaction analysis demonstrated a strong repression of B cell specific genes in these E2A-PBX1/Hoxa9 leukemias in addition to Flt3 activation, indicating inhibition of B cell differentiation in combination with enhanced proliferation. Overexpression of Hoxa9 in established E2A-PBX1 mouse leukemic B cells resulted in a growth advantage in vitro, which was also characterized by an enhanced expression of Flt3.
  
  
  CONCLUSIONS
  we show for the first time that Hoxa9 collaborates with E2A-PBX1 in the oncogenic transformation of B cells in a mouse model that involves Flt3 signaling, which is potentially relevant to human disease.
authors.affiliation: Hospital Maisonneuve-Rosemont Research Center, Montreal, QC.
authors.forename: Mona
authors.initials: M
authors.lastname: Hassawi
authors.forename: Elena A
authors.initials: EA
authors.lastname: Shestakova
authors.forename: Marilaine
authors.initials: M
authors.lastname: Fournier
authors.forename: Charles-Étienne
authors.initials: CÉ
authors.lastname: Lebert-Ghali
authors.forename: Gratianne
authors.initials: G
authors.lastname: Vaisson
authors.forename: Héloïse
authors.initials: H
authors.lastname: Frison
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.forename: Ramon
authors.initials: R
authors.lastname: Vidal
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Bijl
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C089847:E2A-Pbx1 fusion protein; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3
keywords: Hox genes; oncogenes; transcription factors; transgenic mouse model