Distinct oncogenic phenotypes in hematopoietic specific deletions of Trp53

Loss of function in the tumor suppressor gene TP53 is the most common alteration seen in human cancer. In mice,p53 deletion in all cells leads predominantly tothedevelopment of T-cell lymphomas,followed by B-cell lymphomas, sarcomas and teratomas. In order to dissect the role of p53 in the hematopoietic system, we generated and analyzedtwo different mouse models deficient for p53. A pan-hematopoietic p53 deletion mouse was created using Vav1-Crebased deletion; and a B-cell-specific deletion mouse was created using a CD19-Cresystem. The Vav1-p53-KO mice predominantly developed T-cell malignancies in younger mice,and myeloid malignancies in older mice. In T-cellmalignancies, there was accelerated thymic cell maturation with overexpression of Notch1and its downstream effectors. CD19-p53-KO mice developed marginal zone expansion in the spleen,followed by marginal zone lymphoma, some ofwhich progressed to diffuse large B-cell lymphomas. Interestingly, marginal zone and diffuse large B-cell lymphomas had a uniquegene expression signaturecharacterized by activation of the PI3K pathway, compared withwild type marginal zone or follicular cells of the spleen.This study demonstrates lineage specific p53 deletion leading to distinctphenotypessecondary to unique gene expression programs set in motion.