Genetic Modeling of B-cell State Transitions for Rational Design of Lymphoma Therapies

Abstract

The use of genomic data to analyze primary endpoints for clinical trials in diffuse large B-cell lymphomas (DLBCL) significantly improved the development of rational drug combinations for genetically defined patient subsets. Recent genetic mouse models and their ability to recapitulate transitions between germinal center exit and memory B-cell characteristics in DLBCL will accelerate the development of rationale-based clinical trials. See related article by Flümann et al., p. 78 (3). See related article by Venturutti et al., (5).

Figure 1.

Oncogenic and tumor suppressor programs in MCD/C5 DLBCL. A, In wild-type B cells, upon excessive activation of BCR-dependent signaling pathways, as seen with oncogenic alterations or autoreactivity, PRDM1 acts as a tumor suppressor by activating the plasma cell program, leading to terminal differentiation and apoptosis. B,MYD88 and CD79B mutations lead to constitutive activation of the BCR-dependent NF-κB pathway. This excessive pathway activation would normally lead to terminal differentiation and apoptosis, which are respectively prevented by PRDM1 loss (or SPIB overexpression) and BCL2 overexpression. As a result, MYD88/CD79B/PRDM1/BCL2 mutant B cells are blocked in a dynamic state between the germinal center light zone and memory phenotypes and are unable to undergo plasmablastic differentiation. This state primes premalignant B cells to accumulate further genetic lesions and fully transform into MCD/C5 DLBCL. Combination of downregulation of the NF-κB pathway with the BTK inhibitor ibrutinib and reactivation of the apoptotic program with the BCL2 inhibitor venetoclax is therefore a promising therapeutic strategy in MCD/C5 DLBCL, as shown in preclinical studies and early-phase clinical trials. Genes labeled in red represent activating lesions, while genes in blue are inactivating lesions. Red bars represent pathway blocks resulting from genetic lesions. Abbreviations: BCR, B-cell receptor; GC, germinal center.