In this paper, we addressed this question using two novel genetic in vivo models: an experimental mouse model that develops B-ALL only in response to natural infection (the “pax5-het” model, which faithfully mimics human disease with respect to disease penetrance, clinical and genomic characteristics), and a complementary mouse model for conditional Aid expression in B-cell precursors. The gene discussed is AICDA; the disease is acute lymphoblastic leukemia.