TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate

Venturutti, Leandro; Teater, Matt; Zhai, Andrew; Chadburn, Amy; Babiker, Leena; Kim, Daleum; Béguelin, Wendy; Lee, Tak C.; Kim, Young‐Jun; Chin, Christopher R.; Yewdell, William T.; Raught, Brian; Phillip, Jude M.; Jiang, Yanwen; Staudt, Louis M.; Green, Michael R.; Chaudhuri, Jayanta; Elemento, Olivier; Farinha, Pedro; Weng, Andrew P.; Nissen, Michael; Steidl, Christian; Morin, Ryan D.; Scott, David W.; Privé, G.G.; Melnick, Ari

doi:10.1016/j.cell.2020.05.049

Cited by 89 publications

(85 citation statements)

References 114 publications

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“…This process may also be relevant to the MCD/cluster 5 subtype of DLBCL (defined based on co-occurence of Myd88 L265P and Cd79b mutations), which has extensive extra-nodal involvement and has one of the lowest survival rates of DLBCL subtypes 134,135 . MBCs were recently found to promote the progression of MCD/cluster 5 DLBCL 136 . A more precise understanding of the pathways that regulate MBC development and survival could offer new opportunities for the design of therapeutics capable of limiting follicular lymphoma and MCD-DLBCL progression.…”

Section: Concluding Remarks and Perspectivementioning

confidence: 99%

Transcriptional regulation of memory B cell differentiation

2020

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During an immune response, B cells that encounter their cognate antigen become activated and differentiate to form short-lived antibody-secreting cells or germinal centre (GC)-independent memory B cells (MBCs). Within the GC, B cells engage with antigen and compete for limiting amounts of T cell help, which is necessary for B cell survival, proliferation and eventual differentiation into plasma cells or GC-derived MBCs 1. The GC is also the primary site in which B cells undergo somatic hypermutation, with B cells that accrue productive mutations preferentially receiving T cell help. The GC response is required for the development of affinity-matured plasma cells and MBCs (Box 1). MBCs are an important component of protective immunity. MBCs are distinguished by their capacity to survive long term and to rapidly differentiate into antibody-secreting cells upon antigen re-encounter. MBCs can also re-enter the GC during recall responses, where they undergo further somatic hypermutation 2-5. MBCs tend to emerge from the GC during the early phases of the GC response and typically display reduced levels of somatic hypermutation and affinity maturation relative to plasma cells 6-8. In the context of viral infections, the reduced mutational load of MBCs allows these cells to maintain enhanced flexibility in their responsiveness to different viral subtypes compared with plasma cells, which tend to be specific for a particular subtype. Indeed, the MBC population contains an elevated fraction of broadly reactive clones relative to the plasma cell pool for numerous pathogens in both mice and humans 9-12. The MBC response comprises multiple subsets, identified based on their expression of CD80 and PDL2, among other markers 5,8 (Box 2). These MBC subsets emerge from the GC at different times and vary in their capacity to re-enter the GC or differentiate into antibody-secreting cells upon antigen re-encounter 5,6. Iterative exposure to cross-reactive viral antigens is an emerging vaccination strategy designed to elicit broadly reactive MBCs capable of mediating heterosubtypic immunity against pathogens such as influenza. The potential efficacy of an iterative vaccination strategy is limited by the relative inefficiency with which most MBC clones re-enter the GC response 13-15. The secondary GC response tends to consist largely of recently activated naive B cells, with only certain MBC subsets possessing the capacity to efficiently re-enter the GC 4,5,16. Currently, it is unclear why the majority of MBCs fail to participate in secondary GC responses. One possibility is that antigen-specific antibodies limit the ability of MBC clones of the same specificity to access antigen and participate in the GC response 4,17. MBCs can arise through both GC-dependent and GC-independent pathways 18-20. GC-independent MBCs largely develop during the early stages of the immune response and contribute to protective immunity against numerous pathogens including Ehrlichia muris and malaria 14,21. GC-independent MBCs can be somatically hypermutated ...

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Section: Concluding Remarks and Perspectivementioning

confidence: 99%

Transcriptional regulation of memory B cell differentiation

2020

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“…Such findings suggest that FL may develop in a stepwise manner, from an ancestral MB-like premalignant progenitor that at an ulterior point becomes locked into a GCB profile (Figure 1b). Further supporting this model, we found that MCD/C5, a class of post-GC DLBCLs with unfavorable clinical outcomes (Chapuy et al 2018, Schmitz et al 2018, also arises through GC reentry (Venturutti et al 2020). In particular, lossof-function (LOF) mutations in TBL1XR1, a subunit of the SMRT/NCOR corepressor complexes central to the GCB program (discussed below), skew GCB cell fate towards an aberrant non-class-switched MB population with increased GC reentry capacity (Venturutti et al 2020).…”

Section: Germinal Center Reentry As a Prominent Lymphomagenesis Mechamentioning

confidence: 59%

The Role of Epigenetic Mechanisms in B Cell Lymphoma Pathogenesis

Venturutti

Melnick

2021

Annu. Rev. Cancer Biol.

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The capacity of the adaptive immune system to respond to antigenic challenges relies on rapid diversification, expansion, and functional specialization of mature B cells. To accomplish this, activated B cells are transiently endowed with phenotypes that would normally be suppressed in somatic cells, such as enhanced proliferative potential and tolerance for genomic instability. Acquisition of these traits, directed by immune signaling cues and orchestrated by transcriptional and epigenetic programs, sets the stage for malignant transformation, often due to somatic mutations targeting epigenetic machinery in B cell lymphomas. This review examines how such mutations hack the epigenome to reprogram the immune response in such a way as to facilitate the emergence of malignant traits, suppress immune surveillance, and ultimately drive transformation and progression of a diverse spectrum of B cell lymphomas. Importantly, these novel mechanisms reveal vulnerabilities that can be harnessed using new forms of epigenetic therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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“…The mutations primarily alter amino acids on the surface of the WD40 barrel structure that are predicted to have a role in protein-protein interactions. Venturutti et al 14 recently modeled these mutations using Tbl1xr1-cKO mice and mice with conditional knock-in of a Tbl1xr1 D370Y mutant allele (Tbl1xr1-D370Y). Using a GCBspecific Cre allele, homozygous cKO and heterozygous Tbl1xr1-D370Y knock-ins were found to have significantly reduced frequencies of GCB cells and smaller GCs after immunization.…”

Section: C5/mcd Subtype Of Dlbcl: Getting In On the Actionmentioning

confidence: 99%

“…7 Therefore, understanding the epigenetic basis for lymphoma is an important challenge due to the high potential for clinical translation that could improve patient outcomes. Here, we discuss recently published (2018-2020) studies [8][9][10][11][12][13][14] and their translational implications.…”

Section: Introductionmentioning

confidence: 99%

Harnessing lymphoma epigenetics to improve therapies

Yang

Green

2020

Blood

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Affinity maturation and terminal differentiation of B cells via the germinal center reaction is a complex multistep process controlled by transcription factors that induce or suppress large dynamic transcriptional programs. This occurs via the recruitment of coactivator or corepressor complexes that epigenetically regulate gene expression by post-translationally modifying histones and/or remodeling chromatin structure. B-cell–intrinsic developmental programs both regulate and respond to interactions with other cells in the germinal center that provide survival and differentiation signals, such as T-follicular helper cells and follicular dendritic cells. Epigenetic and transcriptional programs that naturally occur during B-cell development are hijacked in B-cell lymphoma by genetic alterations that directly or indirectly change the function of transcription factors and/or chromatin-modifying genes. These in turn skew differentiation toward the tumor cell of origin and alter interactions between lymphoma B cells and other cells within the microenvironment. Understanding the mechanisms by which genetic alterations perturb epigenetic and transcriptional programs regulating B-cell development and immune interactions may identify opportunities to target these programs using epigenetic-modifying agents. Here, we discuss recently published studies centered on follicular lymphoma and diffuse large B-cell lymphoma within the context of prior knowledge, and we highlight how these insights have informed potential avenues for rational therapeutic interventions.

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TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate

Cited by 89 publications

References 114 publications

Transcriptional regulation of memory B cell differentiation

Transcriptional regulation of memory B cell differentiation

The Role of Epigenetic Mechanisms in B Cell Lymphoma Pathogenesis

Harnessing lymphoma epigenetics to improve therapies

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