Targeting B-cell receptor and PI3K signaling in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic category comprising distinct molecular subtypes characterized by diverse genetic aberrations that dictate patient outcome. As roughly one-third of patients with DLBCL are not cured by current standard chemoimmunotherapy, a better understanding of the molecular pathogenesis is warranted to improve outcome. B-cell receptor (BCR) signaling is crucial for the development, growth, and survival of normal B cells and a substantial fraction of malignant B cells. Various analyses revealed genetic alterations of central components of the BCR or its downstream signaling effectors in some subtypes of DLBCL. Thus, BCR signaling and the downstream NF-κB and phosphatidylinositol 3-kinase (PI3K) cascades have been proposed as potential targets for the treatment of patients with DLBCL. As one of the main effectors of BCR activation, PI3K-mediated signals play a crucial role in the pathogenesis and survival of DLBCL. In this review, we summarize our current understanding of BCR signaling with a special focus on the PI3K pathway in DLBCL and how to use this knowledge therapeutically.