High frequency of development of B cell lymphoproliferation and diffuse large B cell lymphoma in Dbl knock-in mice

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2011-05, Vol.89 (5), p.493-504
• Main Authors: Ognibene, Marzia, Barbieri, Ottavia, Vanni, Cristina, Mastracci, Luca, Astigiano, Simonetta, Emionite, Laura, Salani, Barbara, Fedele, Manuela, Resaz, Roberta, Tenca, Claudya, Fais, Franco, Sabatini, Federica, De Santanna, Amleto, Altruda, Fiorella, Varesio, Luigi, Hirsch, Emilio, Eva, Alessandra
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Human Genetics; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Internal Medicine; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - metabolism; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Male; Mice; Molecular Medicine; NIH 3T3 Cells; Original Article; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-010-0712-4

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.