Germinal center‐derived lymphomas: The darkest side of humoral immunity

Abstract

Summary One of the unusual features of germinal center (GC) B cells is that they manifest many hallmarks of cancer cells. Accordingly, most B‐cell neoplasms originate from the GC reaction, and characteristically display abundant point mutations, structural genomic lesions, and clonal diversity from the genetic and epigenetic standpoints. The dominant biological theme of GC‐derived lymphomas is mutation of genes involved in epigenetic regulation and immune receptor signaling, which come into play at critical transitional stages of the GC reaction. Hence, mechanistic studies of these mutations reveal fundamental insight into the biology of the normal and malignant GC B cell. The BCL6 transcription factor plays a central role in establishing the GC phenotype in B cells, and most lymphomas are dependent on BCL6 to maintain survival, proliferation, and perhaps immune evasion. Many lymphoma mutations have the commonality of enhancing the oncogenic functions of BCL6, or overcoming some of its tumor suppressive effects. Herein, we discuss how unique features of the GC reaction create vulnerabilities that select for particular lymphoma mutations. We examine the interplay between epigenetic programming, metabolism, signaling, and immune regulatory mechanisms in lymphoma, and discuss how these are leading to novel precision therapy strategies to treat lymphoma patients.

The role of metabolic checkpoint regulators in B cell survival and transformation

“…1,2 On the flip side, B cells are also known to play pathologic roles in a number of diseases including autoimmune disorders 3,4 and various malignancies. 5 Throughout their life, B cells assume different roles and are exposed to changing environments, which is reflected by dynamic adjustments of their gene expression profile and their metabolic signature. 6,7 B cell development and differentiation are accompanied by transient switching between fairly quiescent stages and stages characterized by rapid proliferation or increased protein secretion.…”

B cell memory: building two walls of protection against pathogens

“…The hope is that more detailed knowledge of the cellular and molecular mechanisms that underlie the generation of protective, long-lived antibody responses and B cell memory will allow the development of safe, effective vaccines for pathogens for which we currently have none. Moreover, such knowledge may have broader benefits; for example, for the development of therapies for both systemic autoimmune disease and B cell tumours that may be, in part, unintended consequences of the drive to generate B cell memory 6,7 .…”

Targeting DNA Repair, Cell Cycle, and Tumor Microenvironment in B Cell Lymphoma

“…The intrinsic force of B cell development—the sequence of V(D)J recombination, CSR, and SHM—can lead to somatic mutations within numerous oncogenes that are associated with lymphomagenesis and their cell-of-origin stemming from the pre-GC, GC, or the post-GC [ 35 , 36 ]. The GC B cell, for instance, is at high risk of undergoing malignant transformation due to genetic lesions that occur in GC-specific DNA remodeling events for Ig affinity maturation [ 37 ]. Beyond mere B cell development, several alterations in DNA repair pathways have been linked to lymphoma susceptibility [ 38 ].…”