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// Changfa Fan 1, * , Jianjun Lyu 2, * , Susu Liu 1, * , Xi Wu 1 , Qianqian Li 2 , Shuya Zhou 1 , Yanwei Yang 2 , Guitao Huo 2 , Qin Zuo 1 , Qingfen Zhu 3 , Ming Guo 3 , Simei Ren 4 , Yanan Guo 5 , Sanlong Wang 2 , Baowen Li 1 , Xue Wang 2 , Yuelei Shen 5 and Youchun Wang 1 1 Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Tiantan Xili, Beijing 100050, China 2 National Center for Safety Evaluation of Drugs, Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing Economic-Technological Development Area, Beijing 100176, China 3 Shandong Institute for Food and Drug Control, High-Tech Zone, Jinan 250101, China 4 Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing 100730, China 5 Beijing Biocytogen Co. LTD, Economic-Technological Development Area, Beijing 101111, China * These authors contributed equally to this work Correspondence to: Youchun Wang, email: wangyc@nifdc.org.cn Keywords: p53 deficient mouse; lymphoma model; MNU induction; C57BL/6 genetic background; T cell lineage Received: November 01, 2016     Accepted: December 03, 2017     Published: January 02, 2018 ABSTRACT Lymphoma is the third most common cancer diagnosed in children and T cell lymphoma has the worst prognosis by clinical observation. So far, a lymphoma model with uniform penetrance has not been available. In this paper, we generated a p53 deficient mouse model by targeting embryo stem cells derived from the C57BL/6 mouse strain. Homozygous p53 deficient mice exhibited more accelerated rate of spontaneous tumorigenesis with a high spontaneous occurrence rate (93.3%) of malignant lymphoma. Because tumour models with a high phenotypic consistency are currently needed, we further generated the lymphoma model by single intraperitoneal injection of 37.5 or 75 mg/kg N-methyl-N-nitrosourea (MNU) to p53 deficient mice. Lymphoma and retinal degeneration occurred in 100% of p53 +/- mice administrated higher concentration of MNU, which was much higher than previously reported models. The main anatomic sites of lymphoma were thymus, spleen, bone marrow, and lymph nodes. Both induced and spontaneous lymphomas in the thymus and spleen were stained positive for CD3 antigen. Furthermore, positive CD4 and/or positive CD8 cells were detected by flow cytometry, indicating a T-cell lineage of the lymphomas. The onset time of this uniform lymphoma model was from 13 to 17 weeks after the administration of MNU accompanied by the second time of weight loss. Based on our observations and previous data, we hypothesised that mice with the B6 background are prone to lymphomagenesis. This model could be used to study the mechanisms of lymphomagenesis, to select new drugs, and to improve the reproducibility of experimental results.

WITHDRAWN: A uniform thymic malignant lymphoma model established with C57BL/6 p53 gene deficient mice