Synergistic activity of Card11 mutant and Bcl6 in the development of diffuse large B‐cell lymphoma in a mouse model

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma; it derives from germinal center B cells. Although DLBCL harbors many genetic alterations, synergistic roles between such alterations in the development of lymphoma are largely undefined. We previously established a mouse model of lymphoma by transplanting gene‐transduced germinal center B cells into mice. Here, we chose one of the frequently mutated genes in DLBCL, Card11 mutant, to explore its possible synergy with other genes, using our lymphoma model. Given that BCL6 and BCL2 expression and/or function are often deregulated in human lymphoma, we examined the possible synergy between Card11, Bcl6, and Bcl2. Germinal center B cells were induced in vitro, transduced with Card11 mutant, Bcl6, and Bcl2, and transplanted. Mice rapidly developed lymphomas, with exogenously transduced Bcl2 being dispensable. Although some mice developed lymphoma in the absence of transduced Bcl6, the absence was compensated by elevated expression of endogenous Bcl6. Additionally, the synergy between Card11 mutant and Bcl6 in the development of lymphoma was confirmed by the fact that the combination of Card11 mutant and Bcl6 caused lymphoma or death significantly earlier and with higher penetrance than Card11 mutant or Bcl6 alone. Lymphoma cells expressed interferon regulatory factor 4 and PR domain 1, indicating their differentiation toward plasmablasts, which characterize activated B cell‐like DLBCL that represents a clinically aggressive subtype in humans. Thus, our mouse model provides a versatile tool for studying the synergistic roles of altered genes underlying lymphoma development. Genomic abnormalities of CARD11 and BCL6 are frequently observed in human diffuse large B cell lymphoma. Although abnormalities of the two genes often co‐exist in patient samples, their synergistic activity in the development of lymphoma has not been explored. This is the first report showing collaboration of Card11 mutant and Bcl6 in lymphomagenesis using a mouse model.