II. Therapy of DLBCL based on genomics

The activated B-cell-like (ABC) and germinal centre B-cell-like (GCB) subtypes of diffuse large B-cell lymphoma (DLBCL) were defined by their apparent derivation from different stages of B-cell differentiation and their differential response to chemotherapy [1]. With current chemotherapy supplemented with Rituximab, the ABC DLBCL subtype remains less curable [2,3], necessitating new approaches to its treatment. The view that the ABC and GCB subtypes represent molecularly distinct diseases has been underscored by studies of translocations, genomic copy number changes and somatic mutations (reviewed in ref. [4]). Translocation of BCL2 is restricted to GCB DLBCL, whereas translocation of BCL6 is three times more common in ABC DLBCL. ABC DLBCL is characterized by recurrent deletions of the INK4a/Arf, PRDM1 and TNFAIP3 loci and gain/amplification of the SPIB and BCL2 loci. GCB DLBCL, on the other hand, is characterized by recurrent amplification of the mIR-17-19 microRNA cluster and deletion of PTEN, both of which activate the PI[3] kinase pathway. Somatic mutations in CD79B and MYD88 are frequent ABC DLBCL, whereas GCB DLBCL sustains mutations in EZH2, TNFRSF14, GNA13, SGK1 and BCL2 that are not found in ABC DLBCL. Thus, the derivation of these DLBCL subtypes from different stages of B-cell differentiation [1] appears to dictate different stereotyped genetic pathways to malignancy. Treatment strategies have emerged from a regulatory pathway-centric view of ABC DLBCL. Activation of the anti-apoptotic NF-kB pathway appears to be a universal feature of ABC DLBCL [5]. Besides potently blocking apoptosis, NF-kB induces expression of IRF4, which acts together with SPIB to promote plasmacytic differentiation. Another obligate genetic event in ABC DLBCL appears to be inactivation of Blimp-1, a key regulator of tumour plasmacytic differentiation. The requirement for Blimp-1 inactivation may be to cause an accumulation of plasmablastic cells that could be the precursors to ABC DLBCL.