title: Determining the contribution of NPM1 heterozygosity to NPM-ALK-induced lymphomagenesis.
abstract: Heterozygous expression of Nucleophosmin (NPM1) predisposes to hematological malignancies in the mouse and cooperates with Myc in lymphomagenesis. NPM1 is therefore regarded as a haploinsufficient tumor suppressor. Heterozygous loss of NPM1 occurs as a result of the t(2;5), which generates the oncogenic fusion tyrosine kinase, NPM-anaplastic lymphoma kinase (ALK), a molecule underlying the pathogenesis of anaplastic large cell lymphoma (ALCL). Given the aforementioned role of NPM1 as a tumor suppressor, we hypothesized that NPM1 heterozygosity would cooperate with NPM-ALK in lymphomagenesis. In the event, we observed no difference in tumor latency, incidence or phenotype in NPM-ALK-transgenic mice heterozygous for NPM1 relative to transgenic mice expressing both NPM1 alleles. We propose that although the t(2;5) simultaneously reduces NPM1 allelic dosage and creates the NPM-ALK fusion protein, the two events do not cooperate in the pathogenesis of ALCL in our mouse model. These data indicate that a tumor-suppressive role for NPM1 may depend on cellular and/or genetic context.
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Fiona K E
authors.initials: FK
authors.lastname: Mduff
authors.forename: C Elizabeth
authors.initials: CE
authors.lastname: Hook
authors.forename: Reuben M
authors.initials: RM
authors.lastname: Tooze
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Huntly
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Turner
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D006579:Heterozygote; D006801:Humans; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases