title: Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis.
abstract: Fbxo7 is an unusual F box protein that augments D-type cyclin complex formation with Cdk6, but not Cdk4 or Cdk2, and its over-expression has been demonstrated to transform immortalised fibroblasts in a Cdk6-dependent manner. Here we present new evidence in vitro and in vivo on the oncogenic potential of this regulatory protein in primary haematopoietic stem and progenitor cells (HSPCs). Increasing Fbxo7 expression in HSPCs suppressed their colony forming ability in vitro, specifically decreasing CD11b (Mac1) expression, and these effects were dependent on an intact p53 pathway. Furthermore, increased Fbxo7 levels enhanced the proliferative capacity of p53 null HSPCs when they were grown in reduced concentrations of stem cell factor. Finally, irradiated mice reconstituted with p53 null, but not wild-type, HSPCs expressing Fbxo7 showed a statistically significant increase in the incidence of T cell lymphoma in vivo. These data argue that Fbxo7 negatively regulates the proliferation and differentiation of HSPCs in a p53-dependent manner, and that in the absence of p53, Fbxo7 expression can promote T cell lymphomagenesis.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Lomonosov
authors.forename: El Kahina
authors.initials: el K
authors.lastname: Meziane
authors.forename: Hongtao
authors.initials: H
authors.lastname: Ye
authors.forename: David E
authors.initials: DE
authors.lastname: Nelson
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Randle
authors.forename: Heike
authors.initials: H
authors.lastname: Laman
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008223:Lymphoma / Q000473:pathology*; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: D044783:F-Box Proteins; C489149:FBXO7 protein, human; D015513:Oncogene Proteins; D019089:Stem Cell Factor; D016159:Tumor Suppressor Protein p53