BCL6 in B-cell lymphomas: old target, new tricks?

BCL6 (B Cell Lymphoma 6) is a master regulator of humoral immunity and is required for the germinal center response. Given this role and its frequent dysregulation in germinal center-derived malignancies, it has remained an attractive target since it was first described over 30 years ago. Like other transcription factors, however, it has been difficult to inhibit due to its lack of conventional binding pockets. With the introduction of specific protein degraders, the potential to target BCL6 clinically is now within reach. In this Perspective, we summarize the roles of BCL6 in B and T cell biology as well as in lymphoma, discuss early efforts at targeting BCL6 and current approaches, and review the results of ongoing early-phase clinical trials of BCL6 degraders. We also explore potential mechanisms of resistance to these agents as well as rational combination therapies.