A novel in vivo model for studying conditional dual loss of BLIMP‐1 and p53 in B‐cells, leading to tumor transformation. Issue 8 (15th June 2017) - Sacco, Antonio
Abstract : The tumor suppressors B‐lymphocyte‐induced maturation protein‐1 (BLIMP‐1) and p53 play a crucial role in B‐cell lymphomas, and their inactivation contributes to the pathogenesis of a wide spectrum of lymphoid malignancies, including diffuse large B‐cell lymphomas (DLBCLs). Patients with activated B‐cell‐like (ABC) DLBCL may present with loss of BLIMP‐1, c‐Myc over‐expression, decreased p53, and poor prognosis. Nevertheless, there is a lack of in vivo models recapitulating the biology of high‐grade ABC DLBCL. We therefore aimed to develop an in vivo model aiming to recapitulate the phenotype observed in this cohort of patients. A Cre‐Lox approach was used to achieve inactivation of both p53 and BLIMP‐1 in murine B‐cells. Contextual ablation of BLIMP‐1 and p53 led to development of IgM‐positive B‐cell lymphoma with an aggressive phenotype, supported by c‐Myc up‐regulation, and accumulation of somatic mutations, as demonstrated by whole exome sequencing. Sensitivity of B‐tumor cells to BTK inhibition was demonstrated. This model mirrors what reported in patients with ABC DLBLC, and therefore represents a novel model for studying the biology of ABC‐DLBCL harboring the dual loss of BLIMP‐1/p53 and c‐Myc over‐expression.