title: High frequency of development of B cell lymphoproliferation and diffuse large B cell lymphoma in Dbl knock-in mice.
abstract: Dbl is the prototype of a large family of GDP-GTP exchange factors for small GTPases of the Rho family. In vitro, Dbl is known to activate Rho, Rac, and Cdc42 and to induce a transformed phenotype in murine fibroblasts. We previously reported that Dbl-null mice are viable and fertile but display defective dendrite elongation of distinct subpopulations of cortical neurons, suggesting a role of Dbl in controlling dendritic growth. To gain deeper insights into the role of Dbl in development and disease, we attempted a knock-in approach to create an endogenous allele that encodes a missense-mutation-mediated loss of function in the DH domain. We generated, by gene targeting technology, a mutant mouse strain by inserting a mutagenized human proto-Dbl cDNA clone expressing only the Dbl N terminus regulatory sequence at the starting codon of murine exon 1. Animals were monitored over a 21-month period, and necropsy specimens were collected for histological examination and immunohistochemistry analysis. Dbl knock-in mice are viable and did not manifest either decreased reproductive performances or gross developmental phenotype but revealed a reduced lifespan compared to wild-type (w.t.) mice and showed, with aging, a B cell lymphoproliferation that often has features of a frank diffuse large B cell lymphoma. Moreover, Dbl knock-in male mice displayed an increased incidence of lung adenoma compared to w.t. mice. These data indicate that Dbl is a tumor susceptibility gene in mice and that loss of function of Dbl DH domain by genetic missense mutations is responsible for induction of diffuse large B cell lymphoma.
authors.affiliation: Laboratory of Molecular Biology, G. Gaslini Institute, Largo Gaslini 5, Genoa, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Ognibene
authors.forename: Ottavia
authors.initials: O
authors.lastname: Barbieri
authors.forename: Cristina
authors.initials: C
authors.lastname: Vanni
authors.forename: Luca
authors.initials: L
authors.lastname: Mastracci
authors.forename: Simonetta
authors.initials: S
authors.lastname: Astigiano
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.forename: Barbara
authors.initials: B
authors.lastname: Salani
authors.forename: Manuela
authors.initials: M
authors.lastname: Fedele
authors.forename: Roberta
authors.initials: R
authors.lastname: Resaz
authors.forename: Claudya
authors.initials: C
authors.lastname: Tenca
authors.forename: Franco
authors.initials: F
authors.lastname: Fais
authors.forename: Federica
authors.initials: F
authors.lastname: Sabatini
authors.forename: Amleto
authors.initials: A
authors.lastname: De Santanna
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Alessandra
authors.initials: A
authors.lastname: Eva
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C512843:Mcf2 protein, mouse; D020741:rho GTP-Binding Proteins