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Abstract
Lymphomas are cancers deriving from lymphocytes, arising preferentially in secondary lymphoid organs, and represent the 6th cancer worldwide and the most frequent blood cancer. The majority of B cell Non-Hodgkin lymphomas (B-NHL) develop from germinal center (GC) experienced mature B cells. GCs are transient structures that form in lymphoid organs in response to antigen exposure of naive B cells, and where B cell receptor (BCR) affinity maturation occurs to promote B cell differentiation into memory B and plasma cells producing high-affinity antibodies. Genomic instability associated with the somatic hypermutation (SHM) and class-switch recombination (CSR) processes during GC transit enhance susceptibility to malignant transformation. Most B cell differentiation steps in the GC are at the origin of frequent B cell malignant entities, namely Follicular Lymphoma (FL) and GCB diffuse large B cell lymphomas (GCB-DLBCL). Over the past decade, large sequencing efforts have provided a great boost in the identification of candidate oncogenes and tumor suppressors involved in FL and DLBCL oncogenesis. Mouse models have been instrumental to accurately mimic in vivo lymphoma-specific mutations and interrogate their normal function in the GC context and their oncogenic function leading to lymphoma onset. The limited access of biopsies during the initiating steps of the disease, the cellular and (epi)genetic heterogeneity of individual tumors across and within patients linked to perturbed dynamics of GC ecosystems make the development of genetically engineered mouse models crucial to decipher lymphomagenesis and disease progression and eventually to test the effects of novel targeted therapies. In this review, we provide an overview of some of the important genetically engineered mouse models that have been developed to recapitulate lymphoma-associated (epi)genetic alterations of two frequent GC-derived lymphoma entities: FL and GCB-DLCBL and describe how those mouse models have improved our knowledge of the molecular processes supporting GC B cell transformation.
Highlights
The germinal center (GC) is a specialized immune structure localized in secondary lymphoid organs—including lymph nodes, tonsils, and spleen—that forms upon antigenic challenge to support the B cell receptor (BCR) affinity maturation process
The GC is canonically divided into two principal zones: the dark zone (DZ), where B cells undergo clonal expansion and accumulate somatic hypermutation (SHM) upon activation-induced-cytidine deaminase (AID) responsible of BCR diversification, and the light zone (LZ), where GC B cell will test their newly acquired mutated Ig for improved affinity to antigen through interaction with immune complex-coated follicular dendritic cells (FDCs) and selection by a limited number of CD4+ T follicular helper cells (TFH) residing in the LZ [2]
Within the LZ, B cells can have several fates: (i) a small subset of high-affinity GC B cells, selected in the LZ, will recycle back in the DZ to undergo further cycles of expansion/mutation/ selection [3, 4], (ii) some selected LZ B cells can directly exit the GC differentiating into effectors such a memory B cells or plasma cells and (iii) LZ cells with low/no affinity BCRs following SHM due to a lack of antigen engagement and subsequent T cell help die by apoptosis (Figure 1)
Summary
Noushin Mossadegh-Keller 1†, Gabriel Brisou 1,2†, Alicia Beyou 1, Bertrand Nadel 1 and Sandrine Roulland 1*. Most B cell differentiation steps in the GC are at the origin of frequent B cell malignant entities, namely Follicular Lymphoma (FL) and GCB diffuse large B cell lymphomas (GCB-DLBCL). The limited access of biopsies during the initiating steps of the disease, the cellular and (epi)genetic heterogeneity of individual tumors across and within patients linked to perturbed dynamics of GC ecosystems make the development of genetically engineered mouse models crucial to decipher lymphomagenesis and disease progression and eventually to test the effects of novel targeted therapies. We provide an overview of some of the important genetically engineered mouse models that have been developed to recapitulate lymphoma-associated (epi)genetic alterations of two frequent GC-derived lymphoma entities: FL and GCB-DLCBL and describe how those mouse models have improved our knowledge of the molecular processes supporting GC B cell transformation
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