Genetic prevention of lymphoma in p53 knockout mice allows the early development of p53-related sarcomas

// Lorena Landuzzi 1, 2 , Marianna L. Ianzano 3 , Giordano Nicoletti 1, 2 , Arianna Palladini 3 , Valentina Grosso 3 , Dario Ranieri 3 , Massimiliano Dall’Ora 3 , Elena Raschi 3 , Roberta Laranga 3 , Marco Gambarotti 4 , Piero Picci 1 , Carla De Giovanni 3 , Patrizia Nanni 3 , Pier-Luigi Lollini 3 1 Laboratory of Experimental Oncology, Rizzoli Orthopedic Institute, Bologna, Italy 2 PROMETEO Laboratory, STB, RIT Department, Rizzoli Orthopedic Institute, Bologna, Italy 3 Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna Italy 4 Anatomy and Pathological Histology, Rizzoli Orthopedic Institute, Bologna, Italy Correspondence to: Patrizia Nanni, e-mail: patrizia.nanni@unibo.it Keywords: p53-KO mice, Rag2KO/Il2rgKO mice, lymphoma, hemangiosarcoma, osteosarcoma Received: August 04, 2014      Accepted: October 27, 2014      Published: November 18, 2014 ABSTRACT Homozygous knockout of p53 in mice leads to early mortality from lymphoma, with almost complete penetrance, thus hampering studies of other tumor histotypes related to p53 alterations. To avoid lymphoma development, we crossed p53 knockout mice (BALB-p53 mice) with alymphocytic BALB/c Rag2−/−;Il2rg−/− (RGKO) mice. We compared the tumor spectrum of homozygous (BALB-p53−/−) and heterozygous (BALB-p53+/−) mice with alymphocytic mice (RGKO-p53−/− and RGKO-p53+/−). Lymphoma incidence in BALB-p53−/− mice exceeded 80%, whereas in RGKO-p53−/− it was strongly reduced. The prevalent tumor of RGKO-p53−/− mice was hemangiosarcoma (incidence over 65% in both sexes, mean latency 18 weeks), other tumors included soft tissue sarcomas (incidence ~10%), lung and mammary carcinomas. Tumor spectrum changes occurred also in p53 heterozygotes, in which lymphomas are relatively rare (~20%). RGKO-p53+/− had an increased incidence of hemangiosarcomas, reaching ~30%, and females had an increased incidence of osteosarcomas, reaching ~20%. Osteosarcomas shared with the corresponding human tumors the involvement of limbs and a high metastatic ability, mainly to the lungs. Specific alterations in the expression of p53-related genes (p16Ink4a, p19Arf, p15Ink4b, p21Cip1) were observed. Genetic prevention of lymphoma in p53 knockout mice led to new models of sarcoma development, available for studies on hemangiosarcoma and osteosarcoma onset and metastatization.