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

Marzia Ognibene, Ottavia Barbieri, Cristina Vanni, Luca Mastracci, Simonetta Astigiano, Laura Emionite, Barbara Salani, Manuela Fedele, Roberta Resaz, Claudya Tenca, Franco Fais, Federica Sabatini, Amleto De Santanna, Fiorella Altruda, Luigi Varesio, Emilio Hirsch, Alessandra Eva

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)493-504
Number of pages12
JournalJournal of Molecular Medicine
Volume89
Issue number5
DOIs
Publication statusPublished - May 2011

Keywords

  • Dbl
  • Diffuse large B cell lymphoma
  • Knock-in mice
  • Lung tumors
  • Small lymphocytic lymphoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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