B-cell receptor signaling in diffuse large B-cell lymphoma

The importance of understanding the genetic and biochemical basis of B-cell receptor (BCR) survival signaling in diffuse large B-cell lymphoma (DLBCL) is underscored by the recent clinical success of agents that target the BCR pathway. DLBCL is composed of multiple distinct molecular subtypes with divergent clinical outcomes. The activated B-cell-like (ABC) subtype is the most aggressive form of DLBCL and is often resistant to standard chemotherapies. ABC DLBCL expresses numerous genes found in antigen-activated B cells, and genetic and pharmacologic studies have demonstrated that ABC DLBCL tumors are addicted to NF-κB activity. The origins of this NF-κB activity remained obscure until RNA interference screens established that the majority of ABC DLBCL cell lines rely on expression of BCR components and downstream signaling effectors for NF-κB activation. Pharmacological inhibition with ibrutinib of Bruton's tyrosine kinase, a kinase that is required for BCR signaling to engage NF-κB, is selectively toxic for ABC DLBCL tumors; a finding that has now been translated to the clinic. These novel targets not only offer a promising new therapy option for ABC DLBCL, but also demonstrate the value of a deep molecular understanding of oncogenic signaling pathways.