Sword Art Online Integral Factor signed V102 Google Drive

Skip Nav Destination

PERSPECTIVES | Nov 12, 2020

The dangers of déjà vu: memory B cells equally the cells of origin of ABC-DLBCLs

Leandro Venturutti,

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell Academy, New York, NY

Search for other works by this author on:

Ari Thou. Melnick

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell Academy, New York, NY

Search for other works by this writer on:

Claret (2020) 136 (twenty): 2263–2274.

Article history

Accepted:

Baronial 27, 2020

First Edition:

September 15, 2020

Abstruse

Activated B-cell (ABC)-lengthened large B-prison cell lymphomas (DLBCLs) are clinically ambitious and phenotypically complex malignancies, whose transformation mechanisms remain unclear. Partially differentiated antigen-secreting cells (plasmablasts) have long been regarded as cells-of-origin for these tumors, despite lack of definitive experimental testify. Recent DLBCL reclassification based on mutational landscapes identified MCD/C5 tumors every bit specific ABC-DLBCLs with unfavorable clinical outcome, activating mutations in the signaling adaptors MYD88 and CD79B, and allowed evasion through mutation of antigen-presenting genes. MCD/C5s manifest prominent extranodal broadcasting and similarities with primary extranodal lymphomas (PENLs). In this regard, recent studies on TBL1XR1, a gene recurrently mutated in MCD/C5s and PENLs, suggest that aberrant retention B cells (MBs), and non plasmablasts, are the truthful cells-of-origin for these tumors. Moreover, transcriptional and phenotypic profiling suggests that MCD/C5s, equally a form, stand for bona fide MB tumors. Based on emerging findings we propose herein a generalized stepwise model for MCD/C5 and PENLs pathogenesis, whereby acquisition of founder mutations in activated B cells favors the evolution of aberrant MBs decumbent to avoid plasmacytic differentiation on recall and undergo systemic broadcasting. Cyclic reactivation of these MBs through persistent antigen exposure favors their clonal expansion and accumulation of mutations, which further facilitate their activation. Equally a consequence, MB-like clonal precursors become trapped in an oscillatory country of semipermanent activation and phenotypic sway that facilitates ulterior transformation and accounts for the extranodal clinical presentation and biology of these tumors. In add-on, we discuss diagnostic and therapeutic implications of a MB cell-of-origin for these lymphomas.

Introduction

Diffuse large B-jail cell lymphomas (DLBCLs) arise from the highly dynamic adaptive immune system, in which B cells transit through various phenotypic/transitional states before differentiating into antibody-secreting cells.¹ Resolving the trajectories through which DLBCLs emerge is important because it could provide the basis for earlier detection of cancerous forerunner lesions and inform rationally designed therapeutic approaches. The get-go molecular classification of DLBCLs grouped tumors into general categories (germinal eye B-cell [GCB]-derived, activated B-cell [ABC]-derived or unclassified) by comparing their transcriptomes to that of broad normal B-cell populations.ⁱⁱ Among these, the cell-of-origin (COO) and transformation mechanisms of ABC-DLBCLs remain generally obscure, despite the fact that these are amid the virtually ambitious and incurable lymphomas.³

Recent studies^{4-half dozen} reclassified DLBCLs based on constellations of genetic lesions, creating an opportunity to refine our understanding of ABC-DLBCL lymphomagenesis. In particular, 2 studies^5,6 described a genetically divers ABC-DLBCL subtype (MCD or Cluster 5 [C5]) that features hallmark activating mutations in MYD88 and CD79B and loss-of-function mutations in the poorly characterized gene TBL1XR1.⁷ MCD/C5s are highly aggressive tumors with unfavorable clinical event, frequent extranodal dissemination, and immune surveillance evasion.^4,vi Indeed, MCD/C5 genomic landscapes strikingly resemble that of primary extranodal lymphomas (PENLs).^viii,9 PENLs reflect an farthermost DLBCL presentation, in that they occupy extranodal and even immune-privileged sites, such every bit the central nervous organisation (CNS), vitreo-retina, or testes, without prior growth in lymphoid organs.¹⁰ Curiously, neither GCBs nor plasma cells (PCs) normally home to these tissues, raising questions about the origin of these tumors inside the complex milieu of B-cell populations.

Despite their elusive origins, ABC-DLBCLs are thought to derive from B cells that have transited through a germinal center (GC) reaction¹¹ (Table one), considering B-jail cell receptors (BCRs) in these tumors bear witness evidence of somatic hypermutation (SHM), a process generally believed to be GCB specific.¹ The fact that these tumors ofttimes nowadays an immunoblastic histology¹² and express the transcription factor (TF) IRF4,¹³ required for PC differentiation and survival,^fourteen,15 led to a widely accepted notion that ABC-DLBCLs originate from plasmablasts (PBs; PC precursor cells). However, recent mass cytometry profiling of MCD/C5 clinical specimens suggests that, instead, these more closely recapitulate a memory B jail cell (MB)-like phenotype.⁷ Indeed, MCD/C5 transcriptional profiles were found to be more closely related to normal forerunner MB populations and depleted for Pb¹⁶ or PC⁴ signatures. Furthermore, modeling TBL1XR1 mutations in mice led to the unexpected discovery that MCD/C5s might develop through cyclic and repetitive reactivation of MB subpopulations.⁷ These data advise that MCD/C5s are actually tumors of highly malignant and aggressive MBs. This perspective volition address the implications of these novel findings and advise a generalized model for MCD/C5 and PENL pathogenesis, providing a rationale for the distinctive clinical features of these tumors and highlighting potential new therapeutic approaches. Of note, recent studies on N1 DLBCLs^4,sixteen (another ABC-DLBCL subclass) or ABC-DLBCLs as a whole^sixteen also pointed to MBs as their closest normal analogue, suggesting that aspects of the models herein could exist generalized to ABC-DLBCLs beyond MCD/C5s.

Table i.

Glossary of terms related to B-cell immune responses

Term	Definition
AID (AICDA)	Enzyme responsible for driving the somatic hypermutation and class switch recombination mechanisms in activated B cells, both of which contribute to B-cell receptor diversification.
Affinity maturation	Process by which GCBs develop B-jail cell receptors with increased antigen analogousness through repeated rounds of diversification, competitive selection, and clonal expansion.
Anergy	Status in which mature B cells persist in periphery simply are poorly responsive to antigen, responsible for silencing self-reactive B cells. Anergy loss contributes to autoimmune disorders.
Antigen or molecular mimicry	Phenomena in which sequence similarities betwixt foreign and self-antigens are sufficient to result in the cross-activation of auto-reactive B cells by pathogen-derived antigens.
Antigen presentation	Surveillance process, essential for T-cell activation, in which T cells screen short peptide antigens displayed on the surface of other cells.
B-prison cell receptor	Membrane-bound immunoglobulin-type receptor, acquired early during B-cell development, that recognizes and binds specific antigens causing activation of mature B cells.
B-cell receptor or antibody repertoire	Collection of B-cell receptors/immunoglobulin sequences expressed by a given population of B cells.
Grade switch recombination/isotype switching	DNA recombination procedure past which the B-cell receptor constant portion is exchanged in mature activated B prison cell, generating functional variety while maintaining antigen specificity.
Clonal precursor cells	Genetically distinct subpopulations of B cells thought to clonally derive from a single founding cell which, following acquisition of one or more somatic mutations, gained a disproportionate proliferative advantage over other mature B-cell populations.
Follicular dendritic cells	Nonhematopoietic stromal cells in B-prison cell follicles and GCs that retain antigens at their prison cell surface in a manner crucial to the selection of B cells expressing high-affinity antigen receptors.
Germinal center reaction	Transient immune structures formed in lymphoid organs, in which activated B cells proliferate, mutate their B-cell receptors, and differentiate to generate high-affinity antibodies and immunological retention.
Immune synapse	Specialized cell–jail cell junction between T cells and antigen-presenting cells, such as GCBs, that allows focal common interaction via soluble and membrane-bound factors.
Astray mutations	Besides known equally aberrant somatic hypermutation (aSHM). Desultory mutations introduced by Aid in loci beyond the B-prison cell receptor, as a byproduct of the somatic hypermutation machinery in activated B cells.
Think response	Adaptive allowed reaction mounted by retentiveness B cells on re-meet with identical or closely related antigenic challenges. These secondary responses tend to be faster and enhanced compared with original/primary allowed responses.
Self-reactivity	Recognition of autologous antigens by a B-prison cell receptor, potentially capable of evoking a pathogenic allowed response by the host.
Somatic hypermutation	Mechanism of B-cell receptor sequence diversification through locus-directed Dna mutagenesis, catalyzed by the enzyme AID in activated mature B cells.
T-follicular helper cells	Specialized subset of CD4+ T-cells essential for GC formation and maintenance, affinity maturation, and development of most loftier-analogousness antibodies and memory B cells.

Term	Definition
Help (AICDA)	Enzyme responsible for driving the somatic hypermutation and class switch recombination mechanisms in activated B cells, both of which contribute to B-cell receptor diversification.
Analogousness maturation	Process by which GCBs develop B-cell receptors with increased antigen affinity through repeated rounds of diversification, competitive selection, and clonal expansion.
Anergy	Condition in which mature B cells persist in periphery but are poorly responsive to antigen, responsible for silencing self-reactive B cells. Anergy loss contributes to autoimmune disorders.
Antigen or molecular mimicry	Phenomena in which sequence similarities betwixt foreign and self-antigens are sufficient to result in the cantankerous-activation of auto-reactive B cells by pathogen-derived antigens.
Antigen presentation	Surveillance process, essential for T-jail cell activation, in which T cells screen short peptide antigens displayed on the surface of other cells.
B-cell receptor	Membrane-jump immunoglobulin-type receptor, acquired early during B-jail cell development, that recognizes and binds specific antigens causing activation of mature B cells.
B-prison cell receptor or antibody repertoire	Drove of B-cell receptors/immunoglobulin sequences expressed by a given population of B cells.
Course switch recombination/isotype switching	DNA recombination process by which the B-cell receptor constant portion is exchanged in mature activated B cell, generating functional diversity while maintaining antigen specificity.
Clonal precursor cells	Genetically singled-out subpopulations of B cells idea to clonally derive from a single founding cell which, following conquering of one or more somatic mutations, gained a disproportionate proliferative advantage over other mature B-cell populations.
Follicular dendritic cells	Nonhematopoietic stromal cells in B-prison cell follicles and GCs that retain antigens at their cell surface in a manner crucial to the selection of B cells expressing high-affinity antigen receptors.
Germinal heart reaction	Transient immune structures formed in lymphoid organs, in which activated B cells proliferate, mutate their B-cell receptors, and differentiate to generate loftier-affinity antibodies and immunological memory.
Immune synapse	Specialized cell–jail cell junction between T cells and antigen-presenting cells, such as GCBs, that allows focal common interaction via soluble and membrane-spring factors.
Off-target mutations	As well known as aberrant somatic hypermutation (aSHM). Sporadic mutations introduced by AID in loci beyond the B-prison cell receptor, as a byproduct of the somatic hypermutation mechanism in activated B cells.
Recall response	Adaptive immune reaction mounted past retention B cells on re-encounter with identical or closely related antigenic challenges. These secondary responses tend to be faster and enhanced compared with original/principal immune responses.
Self-reactivity	Recognition of autologous antigens by a B-prison cell receptor, potentially capable of evoking a pathogenic immune response by the host.
Somatic hypermutation	Mechanism of B-cell receptor sequence diversification through locus-directed DNA mutagenesis, catalyzed by the enzyme AID in activated mature B cells.
T-follicular helper cells	Specialized subset of CD4+ T-cells essential for GC formation and maintenance, affinity maturation, and development of most high-affinity antibodies and memory B cells.

Features that define MBs as lymphoma cells-of-origin

MBs are phenotypically and functionally diverse cells that provide durable responsiveness to immunologic challenges, enabling faster and enhanced immunity on re-encounter with the same or closely related antigens.¹⁷ MBs are long-lived and can persist for decades,¹⁸ retain self-renewal potential when activated,^xix and share gene expression programs with long-term hematopoietic stem cells.²⁰ Conversely, about PCs generated during primary immune responses extinguish shortly after resolution, with only a small fraction persisting as long-lived terminally differentiated cells that abode to the bone marrow (BM).²¹ These traits point to MBs as more suitable vessels for lengthy stepwise lymphomagenesis mechanisms (Figure one).

Effigy ane.

Features that define MBs as lymphoma COO. Predicted characteristics of MCD/C5 and PENLs clonal precursor cells compared with normal MB and PC defining traits. Given the heterogeneous nature of these populations, detail subclasses of MBs and PCs may deviate to some extent from the norm represented here.

Figure 1.

Features that ascertain MBs as lymphoma COO. Predicted characteristics of MCD/C5 and PENLs clonal precursor cells compared with normal MB and PC defining traits. Given the heterogeneous nature of these populations, detail subclasses of MBs and PCs may deviate to some extent from the norm represented hither.

Close modal

Despite their basal quiescence, MB signaling pathways²² and epigenetic patterning²³ support their prompt reactivation in response to immune signals at lower input thresholds than naive B cells (NBs). On reactivation, MB plasticity allows them to undergo terminal plasmacytic differentiation or seed new GC reactions.¹⁷ Mechanisms determining alternative prison cell fates remain largely unknown, simply well-nigh MBs are biased toward PC differentiation,²⁴ and GC re-entry is infrequent.²⁵ The express subset of MBs that do repopulate new GCs typically maintain an immunoglobulin M (IgM)-type BCR^19,26,27 and are thought to arise early during the primary GC.²⁸ Under normal circumstances, GC re-entry permits farther specification of antibiotic repertoires by having antigen-experienced cells undergo new rounds of affinity maturation, just this machinery tin exist hijacked and exacerbated by MCD/C5 canonical mutations to favor transformation.⁷

Beyond these points, MBs intrinsic chapters to disseminate throughout the body farther supports them equally precursors for PENLs. Unlike long-lived PCs (LLPCs), largely confined to the BM,²¹ MBs visit virtually all tissues searching for their cognate antigens.²⁹ Furthermore, MBs take been shown to access immune-privileged sites in pathologies like multiple sclerosis and autoimmune orchitis,^xxx,31 consistent with the notion that MBs serve as COO for main and secondary extranodal DLBCLs.

Circadian MB reactivation equally a pathogenic mechanism

Lymphomagenesis is likely a stepwise process whereby long-lived premalignant clonal forerunner cells (CPCs) accumulate genetic and epigenetic lesions over time, ultimately leading to immune-evasive lymphoma phenotypes. Such CPCs may arise from the pocket-sized subset of MBs that preferentially repopulate new GC reactions after reactivation.^26,27 Whatever genetic or epigenetic perturbation that favors MB commitment to this recall machinery could foster abnormal outgrowth of MB clones that progressively outcompete NBs and normal MBs at seeding GCs (Effigy 2A).²⁴ This skewing would simultaneously force MBs to endure repeated exposure to activation-induced cytidine deaminase (AID)-mediated SHM, concomitantly favoring the accumulation of off-target somatic mutation³² (Figure 2A), a authentication MCD/C5s.^vi Along these lines, Sungalle et al³³ showed that desultory BCL2 overexpression in murine BM cells, mimicking the t(xiv;18) translocations in follicular lymphoma patients, caused clonal expansion and increased Help-driven mutations in B cells. This phenotype was dependent on repeated antigenic claiming and was attributed to the aberrant survival of BCL2-overexpressing MBs and their cyclic reactivation.³³

Figure two.

Cyclic MB reactivation as a pathogenic mechanism. (A) GC re-entry every bit a lymphomagenesis mechanism. Nether normal conditions, only a limited subset of MBs partake in new GC reactions afterwards reactivation. In the early on stages of malignant transformation, founder mutations, acquired by GCBs equally SHM off-target byproducts or resulting from DNA replication errors, can exacerbate this mechanism by producing a set of aberrant MBs that progressively outcompete NB and wild-type (WT) MBs in seeding new GC reactions, favoring their clonal expansion. Concomitantly, participation in successive GC reactions is predicted to result in cumulative acquisition of further off-target mutations in these cells. Such a procedure is envisioned to take place over long periods of time, ultimately generating an MB-like CPC population. Plasmacytic differentiation, both equally another possible GC output and as alternative cell-fate during MB reactivation, is omitted from the scheme for the sake of simplicity simply is expected to be impaired by founder or secondary mutations. (B) Epigenetic, transcriptional, and phenotypic reprogramming induced past TBL1XR1 mutations. TFs BCL6, BACH2, and BLIMP1 are required for GCB, MB, and PC development, respectively. (i) In WT GCBs, BCL6 and BACH2 demark to the PRDM1 (BLIMP1) locus and repress its expression, blocking PC differentiation. Transient repression of gene enhancers linked to last differentiation by BCL6 and TBL1XR1/SMRT/HDAC3 complexes farther prevents MB and PC formation. (ii) TBL1XR1 mutations, equally probable founder events, reprogram SMRT/HDAC3 binding from BCL6 to BACH2, causing de-repression of genes required for GCB differentiation, and potentiating the BACH2-driven MB program. Continued repression of PRMD1 by BACH2 maintains GCBs away from the PC fate and shuttles them into an aberrant MB-like country, involved in MCD/C5s early transformation.

Figure 2.

Cyclic MB reactivation equally a pathogenic machinery. (A) GC re-entry as a lymphomagenesis mechanism. Under normal weather condition, only a limited subset of MBs partake in new GC reactions later reactivation. In the early stages of malignant transformation, founder mutations, acquired by GCBs as SHM off-target byproducts or resulting from Dna replication errors, can exacerbate this machinery past producing a set of aberrant MBs that progressively outcompete NB and wild-type (WT) MBs in seeding new GC reactions, favoring their clonal expansion. Concomitantly, participation in successive GC reactions is predicted to issue in cumulative acquisition of further off-target mutations in these cells. Such a procedure is envisioned to take place over long periods of time, ultimately generating an MB-like CPC population. Plasmacytic differentiation, both as another possible GC output and as alternative cell-fate during MB reactivation, is omitted from the scheme for the sake of simplicity just is expected to exist dumb by founder or secondary mutations. (B) Epigenetic, transcriptional, and phenotypic reprogramming induced by TBL1XR1 mutations. TFs BCL6, BACH2, and BLIMP1 are required for GCB, MB, and PC development, respectively. (i) In WT GCBs, BCL6 and BACH2 bind to the PRDM1 (BLIMP1) locus and repress its expression, blocking PC differentiation. Transient repression of gene enhancers linked to terminal differentiation past BCL6 and TBL1XR1/SMRT/HDAC3 complexes further prevents MB and PC formation. (ii) TBL1XR1 mutations, equally probable founder events, reprogram SMRT/HDAC3 binding from BCL6 to BACH2, causing de-repression of genes required for GCB differentiation, and potentiating the BACH2-driven MB plan. Connected repression of PRMD1 past BACH2 maintains GCBs away from the PC fate and shuttles them into an aberrant MB-like country, involved in MCD/C5s early transformation.

Close modal

Follicular lymphomas are indolent tumors reflecting a GCB phenotype.³⁴ Instead, MCD/C5 DLBCLs are highly ambitious tumors composed of malignant MBs that seem to originate at least in office from a singled-out and highly aberrant grade of MB cyclic re-entry.⁷ Specifically, focal deletions or somatic mutations in TBL1XR1, a subunit of SMRT/NCOR1 corepressor complexes,³⁵ skew GCB jail cell fate toward an IgM⁺ MB population, with increased GC re-entry capacity.⁷ TBL1XR1 genetic lesions likely represent founder events in MCD/C5 human tumors, as per timing analysis of genetic drivers,⁶ supporting a office for these alterations in early transformation. TBL1XR1 dysfunction mediates these effects by impairing association of the SMRT/NCOR1 complex with the GCB transcriptional repressor BCL6, instead inducing its bounden to the TF BACH2,⁷ to drive GCBs toward the MB fate³⁶ (Figure 2B). This pro-BACH2 effect simultaneously blocks GCBs from forming PCs by repressing PRDM1,⁷ a key PC TF³⁷ (Figure 2B).

MCD/C5s and PENLs harbor peculiarly high Aid-driven mutation brunt.^vi,38,39 Accordingly, after repeated antigenic challenges, TBL1XR1-deficient mice develop ambitious MCD/C5-like lymphomas that present very high levels of Assistance-induced immunoglobulin SHM and astray mutations in MCD/C5 genes, such as PIM1.⁷ Notably, extranodal tumors showed the highest burden of mutations compared with nodal tumors in the aforementioned animals or Tbl1xr1 ^WT lymphomas.^vii These observations support the idea that progressive mutation accumulation in MBs leads to MCD/C5 lymphomagenesis. Importantly, immune profiling of MCD/C5 clinical specimens revealed distinctive MB-similar traits, including CD38 downregulation and upregulation of CD27, even in TBL1XR1 ^WT tumors.⁷ This suggests that different combinations of mutations in these tumors may follow similar transformation paths through expansion and dissemination of cancerous MBs.

Antigenic challenges driving MB reactivation and lymphomagenesis

The to a higher place mechanism implies that MCD/C5 CPCs require multiple rounds of reactivation. ABC-DLBCLs rely on nuclear factor-κB (NF-κB) signaling for survival and proliferation,⁴⁰ and MCD/C5s and PENLs present recurrent mutations in Toll-like receptor (TLR) and BCR signaling mediators (eg, MYD88 and CD79B), contributing to the chronic activation of this pathway.^5,6 Interestingly, clinical trials with BCR pathway inhibitors also showed BCR signaling dependency in ABC-DLBCLs that do not harbor these mutations,⁴¹ suggesting possible involvement of nongenetic mechanisms. In this regard, persistent antigen exposure, in the context of (i) self-reactivity or (2) chronic/recurrent infections, could account for both persistent BCR activation in established tumors and MB reactivation during lymphomagenesis:

BCR activation through a self-reactive component

Autoimmune diseases, such equally systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome, are significant risk factors for DLBCL.^42,43 Notably, MCD/C5-similar mutations were recently identified in B cells producing pathogenic autoantibodies in Sjögren syndrome patients,⁴⁴ suggesting the involvement of like CPC populations amongst these diseases. Further supporting a role for machine-reactivity in MCD/C5 transformation and survival, the BCR repertoires of these tumors are differentially enriched for the cocky-reactive variant VH4-34.^4,45,46 Indeed, BCR activation in MCD/C5 cell lines, critical for survival, was shown to depend on self-reactivity confronting components of the B-cell membrane, apoptotic debris, or the BCR itself.⁴⁷ Similarly, increased self-/poly-reactivity has been implicated in primary CNS lymphoma (PCNSL) pathogenesis past facilitating BCR activation by multiple CNS antigens.⁴⁶

The adaptive immune system normally suppresses self-reactive B cells.⁴⁸ However, recent studies have constitute that anergic B cells that recognize both foreign and self-antigens can be activated by immunization and recruited into GCs⁴⁹ (Effigy 3A). These B cells redeem themselves by undergoing SHM and positive option to reduce their self-reactivity while maintaining the chapters to recognize an exogenous antigen⁴⁸ (Figure 3A). In the context of MCD/C5 early pathogenesis, abnormal BCL2 overexpression⁴ may unduly spare self-reactive B cells from jail cell decease. Too, TBL1XR1 mutations could shunt self-reactive B cells into the MB compartment in the absence of T-cell selection (Effigy 3A), considering this mechanism occurs even in the absenteeism of follicular T-helper (T_FH)-driven CD40L signaling.^seven

Figure 3.

Antigenic drivers and immune context of MB reactivation. (A) Aberrant redemption of self-reactive B cells as an early lymphomagenic event. Anergic B cells whose BCRs recognize both self- and strange antigens can exist recruited into GC reactions if activated by the latter. (i) Once within the GC, these B cells can redeem themselves and terminally differentiate if BCR SHM causes them to increment their analogousness for the foreign antigen while minimizing their reaction against cocky. (ii) If the edited BCR does not portray a corrected affinity remainder or if it acquires a stronger cocky-reactive character, GCBs are selected to undergo jail cell death. (iii) Nonetheless, concomitant somatic mutations outside the BCR locus, such every bit those targeting BCL2 and TBL1XR1, hold the potential to aberrantly spare self-reactive cells, allowing them to egress the GC, and persist as MBs capable or reactivating, in a fashion reminiscent of aged/autoimmune B cells ("ABCs," discussed in main text). Persistent reactivation of these cells by self-antigens could and so sustain the malignant transformation process. (B) Alternative niches and compartments for B-jail cell malignant transformation. Although founder mutations in primary and secondary extranodal lymphoma (SENLs) about likely occur in the context of canonical GC reactions, further transformation might follow alternative trajectories. Mixed and strictly non–GC-dependent transformation models might better account for the pathogenesis of PENLs, specially those targeting allowed-privileged organs (discussed in main text).

Figure 3.

Antigenic drivers and immune context of MB reactivation. (A) Aberrant redemption of self-reactive B cells as an early lymphomagenic outcome. Anergic B cells whose BCRs recognize both self- and foreign antigens can be recruited into GC reactions if activated by the latter. (i) Once inside the GC, these B cells can redeem themselves and terminally differentiate if BCR SHM causes them to increase their affinity for the foreign antigen while minimizing their reaction against self. (ii) If the edited BCR does not portray a corrected affinity balance or if it acquires a stronger self-reactive character, GCBs are selected to undergo prison cell death. (iii) However, concomitant somatic mutations outside the BCR locus, such as those targeting BCL2 and TBL1XR1, hold the potential to aberrantly spare self-reactive cells, allowing them to egress the GC, and persist equally MBs capable or reactivating, in a manner reminiscent of aged/autoimmune B cells ("ABCs," discussed in primary text). Persistent reactivation of these cells by cocky-antigens could then sustain the malignant transformation process. (B) Alternative niches and compartments for B-cell cancerous transformation. Although founder mutations in chief and secondary extranodal lymphoma (SENLs) most likely occur in the context of approved GC reactions, further transformation might follow alternative trajectories. Mixed and strictly not–GC-dependent transformation models might improve account for the pathogenesis of PENLs, particularly those targeting allowed-privileged organs (discussed in main text).

Close modal

BCR activation through chronic exposure to strange antigens

Alternatively, long-term BCR stimulation could result from persistent exposure to foreign antigens. For example, chronic hepatitis B (HBV) or C (HCV) virus infections are associated with higher DLBCL incidence.^50,51 In the case of HBV, oncogenic furnishings could outcome from genetic changes introduced by viral integration into the host genome,⁵² similar in HBV-induced carcinomas.⁵³ Even so, HCV is incapable of integrating into the host genome, and the BCR repertoires of HBV-positive DLBCLs appear highly restricted to viral antigens and show SHM burden,⁵² suggesting that tumors arise from the transformation of HBV antigen–selected B cells. Furthermore, the HBV/DLBCL association is not observed in sporadic infections or vaccinations,⁵⁴ suggesting a requirement for persistent antigen exposure in the transformation procedure. Despite HV infections being more than oftentimes associated with NOTCH2-mutated DLBCLs,⁵⁵ whose pathogenesis might differ from MCD/C5s, contempo genetic profiling of DLBCLs in patients with concomitant HBV infections⁵⁶ identified recurrent mutations in PIM1, MYD88, BTG1, and TBL1XR1, suggesting that persistent viral antigen exposure might alternatively favor MCD/C5 pathogenesis.

The self- or foreign antigen scenarios in a higher place are non mutually exclusive, because self-reactivity tin arise from cross-reactive BCRs originally elicited in responses to pathogens, through molecular mimicry.⁵⁷ Beyond the nature of the antigens driving BCR activation, a distinctive characteristic of MCD/C5s and PENLs is their limited class-switch recombination (CSR) and consistent bias toward the IgM isotype.^4,45,46,58 This was proposed to lock tumor cells in a state of elevated Aid activity while simultaneously preventing complete last differentiation.⁴⁵ Notably, the subset of MBs that avoid PC differentiation and repopulate GCs on reactivation are also largely IgM⁺,^26,27 further suggesting their involvement in MCD-DLBCL pathogenesis.

Are canonical GCs required for MCD/C5 lymphomagenesis?

Some other critical question relates to the nature of the allowed-niche context where CPCs go activated. Based on their distinctive Aid-driven genomic footprint, MCD/C5s are idea to originate from GC-transited B cells.^6,46 In this scenario, founder mutations, such as those targeting TBL1XR1, MYD88, or CD79B, would exist caused sporadically by GCBs as byproducts of SHM and proliferation-associated damage.³² Further transformation would crave progressive accumulation of these kinds of mutations by MB subsets. Several lines of prove suggest that this process would crave cyclic re-entry into canonical GC reactions (Figures 2A and 3B). First, Assist-driven SHM is a GC hallmark, allowing the diversification of BCR repertoires during the adaptive immune response.¹ Second, productive synaptic interactions betwixt GCBs and GC-specific stromal populations (ie, T_FH and follicular dendritic cells) are required for GCBs to undergo additional rounds of clonal expansion and SHM.⁵⁹ Third, TBL1XR1 mutant MBs show increased tendency for GC re-entry,⁷ further supporting GC involvement in pathogenesis.

However, a strictly GC-dependent model might be hard to reconcile with PENLs, which develop without apparent prior growth in lymphoid organs, suggesting that at least ulterior transformation steps occur at extranodal, and sometimes immune-privileged, sites (Figure 3B). Recent studies have identified circulating T_FH populations that originate in lymph nodes and disseminate^60-62 and could potentially fulfill functions like to their follicular counterparts at extranodal sites.⁶³ Although T-helper cells and antigen-presenting cells are present in some PCNSLs,⁶⁴ their characteristics and functions have not been elucidated. Moreover, despite the observation of follicle-like structures in the leptomeninges of patients with advanced multiple sclerosis,⁶⁵ definite evidence of ectopic GCs at immune-privileged sites is defective. Equally farther counterpoint to a GC-driven model, TBL1XR1 mutations actually impair the GC reaction past disrupting BCL6 office,⁷ hinting that acquisition of a mature GCB contour is dispensable for transformation.

If MCD/C5 and PENL transformation does not require B cells partaking in approved GCs, in which context are these cells exposed to Assist activity? Interestingly, information technology was recently shown that CSR, an AID-catalyzed mechanism, occurs primarily before activated B cells class GCs.⁶⁶ Additionally, AID can be detected in highly proliferating extrafollicular B cells.⁶⁷ Furthermore, hypermutated non–GC-transited MBs take been identified in patients harboring germline mutations that block CD40L expression in T cells⁶⁸ (required for B-prison cell entry into GCs) and in extrafollicular regions of lymphoid tissues in autoimmunity models.⁶⁹ These studies indicate that antigen and T-jail cell–similar driven signals, just non follicular dendritic cells and T_FH themselves, are required to back up Help part. Along these lines, alternative populations provide stromal back up during allowed responses, such every bit neutrophil B-cell helper cells that facilitate marginal zone B-prison cell activation.⁷⁰ Given that immune-privileged sites restrict lymphocytic access, ane could envision a scenario where local stromal populations, acting as unorthodox surrogates, could support MB-prison cell reactivation, extranodal SHM, and transformation. Indeed, CD40L blockage in mice extinguishes GCs⁷¹ but disproportionately spares Tbl1xr1-mutant MB formation,⁷ suggesting that T_FH might be dispensable for transformation. Farther supporting this observation, transcriptomic analysis of MCD/C5 tumors showed depletion for CD4⁺ and T_FH signatures.⁴

Information technology should be noted that these GC and non-GC activation models are again not necessarily mutually exclusive, considering GC re-entry may be required to establish early on MB-like CPC populations prone to reactivate but dispensable for further mutation accumulation and overt transformation (Figure 3B). The next department will accost what those later on transformation steps might look like and how these would account for MCD/C5s phenotypic presentation.

A putative oscillatory machinery may generate the complex MCD/C5 phenotype

MCD/C5 development involves MB cyclic reactivation and Assistance-driven mutagenesis but may non necessarily require re-entry into approved GCs. Information technology is then logical to consider whether and how these processes could be accelerated to foster repeated rounds of activation and mutagenesis. In normal B cells, strong antigen and mitogen stimulation activate Help transcription,⁷² in a process partially mediated past the TF IRF4.^15,73 Activating mutations in CD79B, PIM1, or MYD88 might confer lower activation thresholds to BCR and TLR date in CPCs that could trigger NF-κB signaling⁴⁰ and IRF4 upregulation, ultimately leading to bursts of proliferation and AID activity.⁷⁴ Indeed, MCD/C5s express elevated levels of IRF4 and its targets,⁷⁵ and ABC-DLBCs exhibit high AID expression.⁷⁴ IRF4 also usually induces PC differentiation^15,73 by repressing BCL6 and inducing PRDM1 (Effigy 4A). This latter aspect of IRF4 function, and CPC differentiation beyond an early Atomic number 82 land, might exist blocked in MCD/C5s past inactivating mutations targeting PRDM1,⁴ or through persistent BACH2-driven PRDM1 transcriptional repression subsequently TBL1XR1 mutations⁷ (Figure 4B).

Figure 4.

An oscillatory lymphomagenesis excursion model. (A) On reactivation, normal MBs undergo concluding plasmacytic differentiation or, less frequently, populate new GC reactions. Key TFs involved in these processes are highlighted at the bottom of the scheme. (B) During MCD/C5 and PENLs transformation, MB-similar CPCs are proposed to get caught in an oscillatory lymphomagenic state. In this scenario, CPCs with low TLR and BCR signaling thresholds become repeatedly reactivated, but unlike normal MBs, their complete differentiation into PC or GCB is blocked past somatic mutations (equally exemplified at the lesser of the scheme). Hence, CPCs instead reversibly swing between early on Lead and pre-GCB states, undergoing bursts of proliferation and AID activation, favoring the acquisition of ulterior mutations needed to achieve allowed evasion, and accounting for the aberrant MB-like presentation of these tumors. (C) WM malignant transformation may follow like or identical initial trajectories than MC/C5s by forming MB-like CPCs. Yet, somatic mutations in WM are expected to block the GCB cell fate but allow plasmacytic differentiation, accounting for the distinctive LLPC-like presentation of these tumors.

Figure 4.

An oscillatory lymphomagenesis circuit model. (A) On reactivation, normal MBs undergo terminal plasmacytic differentiation or, less frequently, populate new GC reactions. Central TFs involved in these processes are highlighted at the bottom of the scheme. (B) During MCD/C5 and PENLs transformation, MB-similar CPCs are proposed to go defenseless in an oscillatory lymphomagenic land. In this scenario, CPCs with low TLR and BCR signaling thresholds become repeatedly reactivated, just unlike normal MBs, their complete differentiation into PC or GCB is blocked past somatic mutations (as exemplified at the bottom of the scheme). Hence, CPCs instead reversibly swing betwixt early Lead and pre-GCB states, undergoing bursts of proliferation and Assistance activation, favoring the acquisition of ulterior mutations needed to achieve immune evasion, and accounting for the aberrant MB-like presentation of these tumors. (C) WM malignant transformation may follow similar or identical initial trajectories than MC/C5s past forming MB-similar CPCs. Notwithstanding, somatic mutations in WM are expected to block the GCB cell fate but allow plasmacytic differentiation, accounting for the distinctive LLPC-like presentation of these tumors.

Close modal

Early precursor (pre)-GCBs express MYC and AID,^66,76 also every bit depression-intermediate levels of BCL6⁷⁷ (Effigy 4A). MYC is required for B cells to accrue metabolic precursors and biomass to support their proliferative bursting, only its expression is repressed in GCBs by their college BCL6 levels.⁷⁶ MCD/C5s feature upregulation of MYC target genes and proliferation programs,⁴ besides as AID and BCL6, consistent with their putative origin from activated MB cells that tin alternatively access a pre–GCB-like status. The fact that many GCB BCL6 target genes are derepressed in MCD/C5s,⁴ perhaps because of mutation-driven immune synapse-like signaling in CPCs or to TBL1XR1 somatic mutations disrupting BCL6 function,^vii farther suggests that acquisition of a mature GCB profile is blocked during transformation. Indeed, despite harnessing proto-oncogenic features from both early Lead and pre-GCB populations, transcriptional profiles of MCD/C5s are depleted for both mature GCB and PC signatures.⁴

A plausible interpretation of these observations is an oscillatory lymphomagenesis circuit (Effigy 4B) whereby highly labile MB-like CPCs, with reduced activation threshold acquired past TLR and BCR activating mutations, undergo repeated rounds of activation-associated consecration of MYC, Assistance, and perhaps BCL6. Notwithstanding, full date of the BCL6 programme is impaired in these cells past mutations such as those in TBL1XR1 that drive CPCs dorsum into the MB prison cell land while also preventing concluding PC differentiation (Figure 4B). The resulting tumors would then reflect the final stages of this process: that of transformed MBs trapped in an activated state.

The oscillatory model proposed here could similarly account for the transformation and presentation of other MB-derived lymphomas, like Waldenström macroglobulinemia (WM) (Figure 4C). WMs are mostly indolent but share features with MCD/C5s. (1) More than 90% of WMs harbor MYD88 ^L265P , the same variant found in MCD/C5s.⁷⁸ (2) WM pathogenesis has been linked to autoimmune disorders and chronic infections.⁷⁹ (three) WMs exhibit SHM burden and express CD27.^79,lxxx (4) WMs testify limited CSR.⁷⁹ (5) Approximately x% of WMs can transform into DLBCLs, eighty% of which evidence extranodal involvement.⁸¹ Still, most WMs are characterized by the accumulation of lymphoplasmacytic cells in the BM and exacerbated monoclonal IgM secretion⁷⁹ in a fashion more reminiscent of LLPCs than MBs. These observations enhance the possibility that WMs could initially follow a common trajectory with MCD/C5s only that the absence of mutations preventing them from oscillating toward plasmablastic phenotypes (like those targeting TBL1XR1 or PRDM1; Figure 4C) would result in ulterior differences in tumor presentation.

An aged/autoimmune B-cell origin for ABC-DLBCLs?

Defining CPC phenotypic traits would constitute a significant step toward the early detection of MCD/C5s and PENLs, considering these could potentially fifty-fifty be screened for in circulation. MBs prone to repopulate GCs are mostly encompassed inside CD27⁺IgM⁺IgD⁻ B cells,^26,27 a minor population in peripheral blood and spleen.⁸² However, even these relatively rare cells are various and heterogeneous in terms of their origin, antigen experiences, and part. Intriguingly, re-entry–decumbent MBs prospectively giving ascent to MCD/C5s⁷ bear notable similarity to aged/autoimmune B cells.^83,84 Aged/autoimmune B cells are observed in elderly female mice and in humans and mice infected with specific pathogens or with autoimmune disorders.⁸⁵ Beyond differences in their phenotypic definition,⁸⁵ aged/autoimmune B cells stain positive for CD11c and express and depend on the TF T-BET (TBX21).⁸⁶ Much like their normal MB counterparts, aged/autoimmune B cells can follow various cell fates on activation, such every bit entering GCs, forming PCs or MBs, or self-renewing.⁸⁷

Additional factors link anile/autoimmune B cells to MCD/C5s. (ane) SHM burden identifies aged/autoimmune B cells as GC-transited cells.⁸⁸ (2) Anile/autoimmune B cells accumulate in the context of persistent BCR activation by chronic infections or cocky-reactivity.^83,89 (3) T-BET induction and aged/autoimmune B cells development and survival are critically dependent on MYD88 signaling.^83,90 (5) Despite T-BET's role in promoting CSR, a significant fraction of aged/autoimmune B cells remain IgM⁺.⁸⁵ (4) Anile/autoimmune B cells produce and secrete interleukin-10,⁸⁴ similar to ABC-DLBCLs.⁹¹ These considerations enhance the possibility that MCD/C5 DLBCLs may develop from MB-like CPCs that are similar to, or indistinguishable from, anile/autoimmune B cells, as further suggested by the presence of canonical ABC-DLBCL somatic mutations in MBs of patients with autoimmune disorders.⁴⁴ These findings highlight the need to identify features that might be predictive of anile/autoimmune B cells/MB/CPCs transformation to overt MCD/C5s and PENLs.

Clonal expansion under the (immune) radar

Avoiding immune eradication by becoming undetectable or resistant to cytotoxic attacks is a prerequisite for lymphomagenesis. Even so, normal MBs are highly attuned to the immune system, scouting tissues for foreign antigens and closely collaborating with T cells.²⁹ Such behavior would presumably restrict the power of MB-like CPCs to grow in an unrestricted fashion, meaning they must find ways to elude T-cell surveillance and clearance. On the one paw, lymphomas targeting immune-privileged sites might circumvent controls by taking advantage of the selective access granted by these organs to immune cells.⁹² In other words, malignant precursors that manage to infiltrate these sites, every bit MBs are known to do in autoimmune disorders,^30,31 could harness natural barriers to partially isolate themselves from immune surveillance. Even so, this is non plenty to completely avoid immune clearance,⁶⁴ and most MCD/C5s exist outside of immune-privileged sites,^4,vi indicating that boosted strategies must come into play. Along these lines, information technology was shown that ∼75% of MCD/C5s acquire genomic lesions that reduce antigen presentation (through MHC-I or TAP1 inactivation) or directly impairing natural killer and T-cell activation (through CD58 inactivation and PD-L1 or PD-L2 gene fusions and overexpression).⁴ The loftier prevalence of these alterations suggests these are critically needed for CPCs to give rise to full-blown lymphomas. Beyond these straight hits, MYD88 activating mutations can also contribute to allowed evasion by inducing the expression of the T-cell inhibitory molecule PD-L1.⁹³ Additionally, MYD88 genomic lesions could heighten production of interleukin-10,⁹⁴ whose expression is elevated in MCD/C5s.⁴ This cytokine promotes autocrine tumor growth through JAK2/STAT3 activation⁹¹ but can likewise restrict proinflammatory cytokine production, costimulatory molecule expression, and antigen presentation,⁹⁵ ultimately terminating T-jail cell responses and facilitating tumor allowed evasion.

Implications of an MB COO for targeted therapies

Although R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin], vincristine sulfate [oncovin], and prednisone) significantly improved overall DLBCL prognosis, 30% to 50% of patients evidence resistance or relapse subsequently treatment,⁹⁶ with MCD/C5s showing the worst response and outcome.^5,6 The clinical management of extranodal DLBCLs presents additional challenges, given their particular anatomic localization,⁹⁷ highlighting the need for rationally designed subtype-specific treatments. BCR-dependent NF-κB activation in MCD/C5s has prompted interest in agents targeting this pathway, such as ibrutinib and lenalidomide.⁹⁸ Ibrutinib targets BTK kinase, which links BCR and TLR/MYD88-driven NF-κB activation, and clinical trials with this drug accept shown promising results for MCD/C5s⁴¹ and PCNSL.^99,100 All the same, BTK inhibitors alone do not command MCD/C5s, making information technology necessary to target additional biological vulnerabilities in these tumors. One approach to circumventing signaling bypass mechanisms is to target boosted nodes of the BCR and MYD88 signaling pathways, such equally IRAK4,¹⁰¹ MALT1,^102,103 and PI3K/mTOR.^100,104

Complementary to these strategies, an MB COO for extranodal tumors provides alternative targets. The histone deacetylase HDAC3 collaborates with BCL6 in shaping the chromatin landscape and transcriptome of GCBs and GCB-DLBCLs.^105-107 Accordingly, selective inhibition of HDAC3 was shown to be an efficient targeted therapy against GCB-DLBCLs harboring mutations in the histone acetyltransferase CREBBP.¹⁰⁸ TBL1XR1 mutation drives MCD/C5s through abnormal recruitment of SMRT/HDAC3 complexes to BACH2,⁷ suggesting that MCD/C5s might also be dependent on HDAC3 office and sensitive to its inhibition. Interleukin-9R (IL-9R) is another potentially interesting target, because it was shown to mediate the aberrant expansion of MB precursors after TBL1XR1 genetic lesions.⁷ Additional studies accept implicated IL-9/IL-9R signaling in MB recall responses¹⁰⁹ and establish a correlation between IL-9R overexpression and worse clinical outcome in a small-scale DLBCL cohort.¹¹⁰ Final, chemokine receptors mediating the homing of CPCs and tumor cells to extranodal sites remain largely unexplored but concur slap-up potential for approaches aimed at blocking dissemination.

As mentioned previously, cytotoxic therapy resistance and relapse are prevalent amongst extranodal lymphomas. Although particular mechanisms may vary, these phenomena could stem from the MB-like character of these tumors. First, the epigenetic and transcriptional plasticity of MBs could be harnessed by tumor cells to acquire molecular resistance mechanisms to therapies, even in the absence of additional somatic mutations. Second, a fraction of CPCs could remain or become dormant/quiescent, like resting MBs, generating a reservoir that withstands the ablation of highly proliferative cells, and is thus able to repopulate the tumor and contribute to the relapsing nature of these disease in a fashion similar to stem jail cell populations in leukemias. Future research endeavors should then focus on identifying these CPCs, understanding their niche, and elucidating ways to eradicate them.

Concluding remarks

Synthesizing data discussed higher up, nosotros propose a modified stepwise model for MCD/C5s and PENLs pathogenesis through the progressive malignant transformation of MB cells (Figure 5). A deeper exploration of MB subpopulations and their abnormal dysregulation is probable to ameliorate our understanding of these diseases and holds additional potential for elucidating the partially overlapping nature of DLBCLs and other immunologic disorders. Collectively, these observations invite us to rethink the way we conceive, diagnose, and care for these oftentimes fatal diseases.

Effigy 5.

Stepwise model for MCD/C5s and PENLs pathogenesis. (one) During normal immune responses, SHM or DNA replication errors stochastically introduce off-target founder mutations in GCBs, favoring the development of an immature long-lived MB population with increased tendency to acquire a GCB-like profile on recall, at the expense of terminal PC differentiation. (2) Cyclic reactivation of these MBs over extended periods of time favors their clonal expansion and increases the chances of acquiring additional off-target mutations. Repeated activation may be driven past a self-reactive BCR or chronic exposure to foreign agents and could occur in the context of canonical GCs or in a GC-independent manner. (3) Founder or secondary-caused mutations, targeting BCR and TLR pathway mediators, lower the immune activation threshold of these MB-like CPCs, driving them into a semipersistent activated state. At this stage, cells are predicted to become less dependent on canonical costimulatory signaling. (4) Persistent activation in the context of MBs intrinsic phenotypic plasticity traps CPCs in a almost cell-democratic oscillatory state, navigating betwixt MB-like, pre-GC–like, and Atomic number 82-similar phases, whereas somatic mutations block full lineage commitment. (5) These CPCs intermittently undergo bursts of proliferation and Assist activation, allowing the acquisition of ulterior genomic lesions that, paired with transcriptional/epigenetic remodeling, enable consummate immune evasion and overt tumor development.

Figure 5.

Stepwise model for MCD/C5s and PENLs pathogenesis. (1) During normal allowed responses, SHM or Dna replication errors stochastically introduce off-target founder mutations in GCBs, favoring the evolution of an young long-lived MB population with increased tendency to acquire a GCB-like profile on recall, at the expense of terminal PC differentiation. (2) Circadian reactivation of these MBs over extended periods of time favors their clonal expansion and increases the chances of acquiring additional off-target mutations. Repeated activation may be driven by a self-reactive BCR or chronic exposure to strange agents and could occur in the context of canonical GCs or in a GC-independent manner. (three) Founder or secondary-acquired mutations, targeting BCR and TLR pathway mediators, lower the allowed activation threshold of these MB-like CPCs, driving them into a semipersistent activated state. At this stage, cells are predicted to become less dependent on canonical costimulatory signaling. (iv) Persistent activation in the context of MBs intrinsic phenotypic plasticity traps CPCs in a most cell-autonomous oscillatory land, navigating between MB-like, pre-GC–like, and Pb-like phases, whereas somatic mutations block full lineage delivery. (5) These CPCs intermittently undergo bursts of proliferation and Assist activation, allowing the acquisition of ulterior genomic lesions that, paired with transcriptional/epigenetic remodeling, enable complete immune evasion and overt tumor evolution.

Close modal

Acknowledgments

This piece of work was supported past grants from the Leukemia & Lymphoma Society (Career Development Program Grant 5469-xviii to L.V., LLS-TRP-6572-19 and LLS-SCOR-7012-16 to A.M.M.), the National Cancer Institute (NCI-R35-CA220499 to A.M.G.), the Chemotherapy Foundation (to A.Grand.1000.), and the Follicular Lymphoma Consortium (to A.M.G.). Cartoons used in figures were adjusted from images in the Servier Medical Art repository, within the terms of the Creative Commons Attribution three.0 Unported License.

Authorship

Contribution: Fifty.V. and A.Yard.M. conceptualized and prepared the figures and manuscript.

Conflict-of-interest disclosure: A.M.1000. receives inquiry funding for Janssen and Sanofi, is on the scientific board of KDAC pharmaceuticals, and has consulted for Constellation, Epizyme and Jubilant. L.Five. declares no competing financial interests.

Correspondence: Ari G. Melnick, Partitioning of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, 413E 69th St, New York, NY 10021; e-mail: amm2014@med.cornell.edu; and Leandro Venturutti, Segmentation of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, 413E 69th St, New York, NY 10021; e-mail: lev2009@med.cornell.edu.

REFERENCES

1.

Cyster

JG

,

Allen

CDC

.

B cell responses: jail cell interaction dynamics and decisions

.

Jail cell

.

2019

;

177

(

3

):

524

-

540

.

2.

Wright

G

,

Tan

B

,

Rosenwald

A

,

Hurt

EH

,

Wiestner

A

,

Staudt

LM

.

A cistron expression-based method to diagnose clinically distinct subgroups of lengthened large B cell lymphoma

.

Proc Natl Acad Sci USA

.

2003

;

100

(

17

):

9991

-

9996

.

3.

Beham-Schmid

C

.

Aggressive lymphoma 2016: revision of the WHO classification

.

Memo

.

2017

;

10

(

4

):

248

-

254

.

4.

Wright

GW

,

Huang

DW

,

Phelan

JD

, et al.

A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications

.

Cancer Jail cell

.

2020

;

37

(

4

):

551

-

568

.

five.

Schmitz

R

,

Wright

GW

,

Huang

DW

, et al.

Genetics and pathogenesis of diffuse big B-cell lymphoma

.

N Engl J Med

.

2018

;

378

(

15

):

1396

-

1407

.

vi.

Chapuy

B

,

Stewart

C

,

Dunford

AJ

, et al.

Molecular subtypes of diffuse big B prison cell lymphoma are associated with singled-out pathogenic mechanisms and outcomes [published corrections in Nat Med. 2018;24:1292 and Nat Med. 2018;24:1290-1291]

.

Nat Med

.

2018

;

24

(

5

):

679

-

690

.

seven.

Venturutti

Fifty

,

Teater

One thousand

,

Zhai

A

, et al.

TBL1XR1 mutations drive extranodal lymphoma by introducing a protumorigenic memory fate

.

Jail cell

.

2020

;

182

(

2

):

297

-

316.e27

.

eight.

Gonzalez-Aguilar

A

,

Idbaih

A

,

Boisselier

B

, et al.

Recurrent mutations of MYD88 and TBL1XR1 in main key nervous system lymphomas

.

Clin Cancer Res

.

2012

;

xviii

(

19

):

5203

-

5211

.

nine.

Chapuy

B

,

Roemer

MG

,

Stewart

C

, et al.

Targetable genetic features of main testicular and primary primal nervous organisation lymphomas

.

Blood

.

2016

;

127

(

7

):

869

-

881

.

x.

Pals

ST

,

de Gorter

DJ

,

Spaargaren

M

.

Lymphoma broadcasting: the other face of lymphocyte homing

.

Blood

.

2007

;

110

(

9

):

3102

-

3111

.

eleven.

Lenz

G

.

Insights into the molecular pathogenesis of activated B-cell-like diffuse big B-jail cell lymphoma and its therapeutic implications

.

Cancers (Basel)

.

2015

;

7

(

ii

):

811

-

822

.

12.

Xie

Y

,

Pittaluga

S

,

Jaffe

ES

.

The histological nomenclature of diffuse big B-cell lymphomas

.

Semin Hematol

.

2015

;

52

(

2

):

57

-

66

.

13.

Alizadeh

AA

,

Eisen

MB

,

Davis

RE

, et al.

Distinct types of diffuse large B-cell lymphoma identified past cistron expression profiling

.

Nature

.

2000

;

403

(

6769

):

503

-

511

.

14.

Tellier

J

,

Shi

Due west

,

Minnich

M

, et al.

Blimp-one controls plasma cell office through the regulation of immunoglobulin secretion and the unfolded poly peptide response

.

Nat Immunol

.

2016

;

17

(

iii

):

323

-

330

.

15.

Klein

U

,

Casola

S

,

Cattoretti

G

, et al.

Transcription cistron IRF4 controls plasma cell differentiation and class-switch recombination

.

Nat Immunol

.

2006

;

7

(

7

):

773

-

782

.

16.

Holmes

AB

,

Corinaldesi

C

,

Shen

Q

, et al.

Unmarried-cell assay of germinal-center B cells informs on lymphoma cell of origin and outcome

.

J Exp Med

.

2020

;

217

(

10

):

e20200483

.

17.

Weisel

F

,

Shlomchik

1000

,

Memory

B

.

Retention B cells of mice and humans

.

Annu Rev Immunol

.

2017

;

35

(

1

):

255

-

284

.

eighteen.

Jones

DD

,

Wilmore

JR

,

Allman

D

.

Cellular dynamics of memory B cell populations: IgM+ and IgG+ memory B cells persist indefinitely equally quiescent cells

.

J Immunol

.

2015

;

195

(

10

):

4753

-

4759

.

19.

Zuccarino-Catania

GV

,

Sadanand

Due south

,

Weisel

FJ

, et al.

CD80 and PD-L2 define functionally singled-out memory B cell subsets that are contained of antibody isotype

.

Nat Immunol

.

2014

;

15

(

seven

):

631

-

637

.

20.

Luckey

CJ

,

Bhattacharya

D

,

Goldrath

AW

,

Weissman

IL

,

Benoist

C

,

Mathis

D

.

Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stalk cells

.

Proc Natl Acad Sci Usa

.

2006

;

103

(

nine

):

3304

-

3309

.

21.

Brynjolfsson

SF

,

Persson Berg

50

,

Olsen Ekerhult

T

, et al.

Long-lived plasma cells in mice and men

.

Forepart Immunol

.

2018

;

ix

:

2673

.

22.

Deenick

EK

,

Avery

DT

,

Chan

A

, et al.

Naive and memory human being B cells have distinct requirements for STAT3 activation to differentiate into antibiotic-secreting plasma cells

.

J Exp Med

.

2013

;

210

(

12

):

2739

-

2753

.

23.

Lai

AY

,

Mav

D

,

Shah

R

, et al.

Dna methylation profiling in homo B cells reveals immune regulatory elements and epigenetic plasticity at Alu elements during B-prison cell activation

.

Genome Res

.

2013

;

23

(

12

):

2030

-

2041

.

24.

Arpin

C

,

Banchereau

J

,

Liu

YJ

.

Retention B cells are biased towards last differentiation: a strategy that may prevent repertoire freezing

.

J Exp Med

.

1997

;

186

(

6

):

931

-

940

.

25.

Mesin

L

,

Schiepers

A

,

Ersching

J

, et al.

Restricted clonality and limited germinal center reentry characterize memory B cell reactivation past boosting

.

Cell

.

2020

;

180

(

one

):

92

-

106

.

26.

Seifert

Thou

,

Przekopowitz

Chiliad

,

Taudien

S

, et al.

Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions

.

Proc Natl Acad Sci USA

.

2015

;

112

(

6

):

E546

-

E555

.

27.

Dogan

I

,

Bertocci

B

,

Vilmont

V

, et al.

Multiple layers of B cell memory with different effector functions

.

Nat Immunol

.

2009

;

10

(

12

):

1292

-

1299

.

28.

Weisel

FJ

,

Zuccarino-Catania

GV

,

Chikina

M

,

Shlomchik

MJ

.

A temporal switch in the germinal middle determines differential output of memory B and plasma cells

.

Amnesty

.

2016

;

44

(

i

):

116

-

130

.

29.

Dhenni

R

,

Phan

TG

.

The geography of memory B jail cell reactivation in vaccine-induced immunity and in autoimmune affliction relapses

.

Immunol Rev

.

2020

;

296

(

1

):

62

-

86

.

30.

Zhao

S

,

Zhu

Westward

,

Xue

S

,

Han

D

.

Testicular defence force systems: immune privilege and innate immunity

.

Cell Mol Immunol

.

2014

;

eleven

(

5

):

428

-

437

.

31.

Blauth

Grand

,

Owens

GP

,

Bennett

JL

.

The ins and outs of B cells in multiple sclerosis

.

Front Immunol

.

2015

;

6

:

565

.

32.

Liu

M

,

Duke

JL

,

Richter

DJ

, et al.

Ii levels of protection for the B cell genome during somatic hypermutation

.

Nature

.

2008

;

451

(

7180

):

841

-

845

.

33.

Sungalee

South

,

Mamessier

E

,

Morgado

E

, et al.

Germinal eye reentries of BCL2-overexpressing B cells drive follicular lymphoma progression

.

J Clin Invest

.

2014

;

124

(

12

):

5337

-

5351

.

34.

Korfi

Thou

,

Ali

S

,

Heward

JA

,

Fitzgibbon

J

.

Follicular lymphoma, a B cell malignancy fond to epigenetic mutations

.

Epigenetics

.

2017

;

12

(

5

):

370

-

377

.

35.

Zhang

J

,

Kalkum

M

,

Chait

BT

,

Roeder

RG

.

The North-CoR-HDAC3 nuclear receptor corepressor circuitous inhibits the JNK pathway through the integral subunit GPS2

.

Mol Cell

.

2002

;

9

(

3

):

611

-

623

.

36.

Shinnakasu

R

,

Inoue

T

,

Kometani

K

, et al.

Regulated selection of germinal-heart cells into the memory B cell compartment

.

Nat Immunol

.

2016

;

17

(

7

):

861

-

869

.

37.

Minnich

Thou

,

Tagoh

H

,

Bönelt

P

, et al.

Multifunctional role of the transcription factor Stuffed-1 in analogous plasma jail cell differentiation

.

Nat Immunol

.

2016

;

17

(

3

):

331

-

343

.

38.

Thompsett

AR

,

Ellison

DW

,

Stevenson

FK

,

Zhu

D

.

V(H) gene sequences from chief primal nervous organisation lymphomas bespeak derivation from highly mutated germinal center B cells with ongoing mutational activity

.

Blood

.

1999

;

94

(

5

):

1738

-

1746

.

39.

Ou

A

,

Sumrall

A

,

Phuphanich

Due south

, et al.

Primary CNS lymphoma normally expresses immune response biomarkers

.

Neurooncol Adv

.

2020

;

2

(

1

):

vdaa018

.

xl.

Davis

RE

,

Dark-brown

KD

,

Siebenlist

U

,

Staudt

LM

.

Constitutive nuclear factor kappaB action is required for survival of activated B cell-like diffuse big B cell lymphoma cells

.

J Exp Med

.

2001

;

194

(

12

):

1861

-

1874

.

41.

Wilson

WH

,

Young

RM

,

Schmitz

R

, et al.

Targeting B prison cell receptor signaling with ibrutinib in diffuse big B cell lymphoma

.

Nat Med

.

2015

;

21

(

viii

):

922

-

926

.

42.

Koff

JL

,

Flowers

CR

.

B cells gone rogue: the intersection of lengthened large B cell lymphoma and autoimmune disease

.

Expert Rev Hematol

.

2016

;

nine

(

6

):

553

-

561

.

43.

Cuttner

J

,

Spiera

H

,

Troy

Thousand

,

Wallenstein

South

.

Autoimmune disease is a risk factor for the development of non-Hodgkin'due south lymphoma

.

J Rheumatol

.

2005

;

32

(

10

):

1884

-

1887

.

44.

Singh

M

,

Jackson

KJL

,

Wang

JJ

, et al.

Lymphoma driver mutations in the pathogenic evolution of an iconic human autoantibody

.

Cell

.

2020

;

180

(

5

):

878

-

894

.

45.

Ruminy

P

,

Etancelin

P

,

Couronné

L

, et al.

The isotype of the BCR every bit a surrogate for the GCB and ABC molecular subtypes in diffuse large B-jail cell lymphoma

.

Leukemia

.

2011

;

25

(

four

):

681

-

688

.

46.

Montesinos-Rongen

Grand

,

Terrao

M

,

May

C

, et al.

The procedure of somatic hypermutation increases polyreactivity for cardinal nervous system antigens in primary fundamental nervous system lymphoma [published online alee of print xix March 2020]

.

Haematologica

.

doi:10.3324/haematol.2019.242701

.

47.

Immature

RM

,

Wu

T

,

Schmitz

R

, et al.

Survival of human lymphoma cells requires B-cell receptor engagement past cocky-antigens

.

Proc Natl Acad Sci USA

.

2015

;

112

(

44

):

13447

-

13454

.

48.

Haynes

BF

,

Verkoczy

50

,

Kelsoe

G

.

Redemption of autoreactive B cells

.

Proc Natl Acad Sci U.s.a.

.

2014

;

111

(

25

):

9022

-

9023

.

49.

Sabouri

Z

,

Schofield

P

,

Horikawa

Thousand

, et al.

Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity

.

Proc Natl Acad Sci USA

.

2014

;

111

(

25

):

E2567

-

E2575

.

fifty.

Visco

C

,

Finotto

S

.

Hepatitis C virus and diffuse large B-cell lymphoma: pathogenesis, behavior and handling

.

World J Gastroenterol

.

2014

;

20

(

32

):

11054

-

11061

.

51.

Rong

X

,

Wang

H

,

Ma

J

, et al.

Chronic hepatitis B virus infection is associated with a poorer prognosis in lengthened large B-cell lymphoma: a meta-assay and systemic review

.

J Cancer

.

2019

;

10

(

15

):

3450

-

3458

.

52.

Deng

50

,

Song

Y

,

Young

KH

, et al.

Hepatitis B virus-associated lengthened large B-cell lymphoma: unique clinical features, poor upshot, and hepatitis B surface antigen-driven origin

.

Oncotarget

.

2015

;

6

(

28

):

25061

-

25073

.

53.

Sung

WK

,

Zheng

H

,

Li

S

, et al.

Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma

.

Nat Genet

.

2012

;

44

(

7

):

765

-

769

.

54.

Huang

CE

,

Yang

YH

,

Chen

YY

, et al.

The impact of hepatitis B virus infection and vaccination on the development of non-Hodgkin lymphoma

.

J Viral Hepat

.

2017

;

24

(

10

):

885

-

894

.

55.

Arcaini

L

,

Rossi

D

,

Lucioni

M

, et al.

The NOTCH pathway is recurrently mutated in diffuse big B-cell lymphoma associated with hepatitis C virus infection

.

Haematologica

.

2015

;

100

(

2

):

246

-

252

.

56.

Ren

West

,

Ye

10

,

Su

H

, et al.

Genetic landscape of hepatitis B virus-associated lengthened large B-jail cell lymphoma

.

Blood

.

2018

;

131

(

24

):

2670

-

2681

.

57.

Rojas

M

,

Restrepo-Jiménez

P

,

Monsalve

DM

, et al.

Molecular mimicry and autoimmunity

.

J Autoimmun

.

2018

;

95

:

100

-

123

.

58.

Lenz

G

,

Nagel

I

,

Siebert

R

, et al.

Aberrant immunoglobulin form switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma

.

J Exp Med

.

2007

;

204

(

iii

):

633

-

643

.

59.

Papa

I

,

Vinuesa

CG

.

Synaptic interactions in germinal centers

.

Front Immunol

.

2018

;

nine

:

1858

.

60.

Zhang

J

,

Liu

Westward

,

Wen

B

, et al.

Circulating CXCR3⁺ Tfh cells positively correlate with neutralizing antibody responses in HCV-infected patients

.

Sci Rep

.

2019

;

ix

(

i

):

10090

.

61.

Vella

LA

,

Buggert

Thousand

,

Manne

S

, et al.

T follicular helper cells in man efferent lymph retain lymphoid characteristics

.

J Clin Invest

.

2019

;

129

(

8

):

3185

-

3200

.

62.

Koutsakos

1000

,

Wheatley

AK

,

Loh

L

, et al.

Circulating T_FH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity

.

Sci Transl Med

.

2018

;

10

(

428

):

eaan8405

.

63.

Vu Van

D

,

Beier

KC

,

Pietzke

LJ

, et al.

Local T/B cooperation in inflamed tissues is supported by T follicular helper-like cells

.

Nat Commun

.

2016

;

seven

:

10875

.

64.

Bashir

R

,

Chamberlain

One thousand

,

Ruby

E

,

Hochberg

FH

.

T-cell infiltration of primary CNS lymphoma

.

Neurology

.

1996

;

46

(

2

):

440

-

444

.

65.

Serafini

B

,

Rosicarelli

B

,

Magliozzi

R

,

Stigliano

E

,

Aloisi

F

.

Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis

.

Brain Pathol

.

2004

;

xiv

(

2

):

164

-

174

.

66.

Roco

JA

,

Mesin

L

,

Binder

SC

, et al.

Class-switch recombination occurs infrequently in germinal centers

.

Immunity

.

2019

;

51

(

2

):

337

-

350

.

67.

Cattoretti

G

,

Büttner

Thou

,

Shaknovich

R

,

Kremmer

E

,

Alobeid

B

,

Niedobitek

G

.

Nuclear and cytoplasmic Assistance in extrafollicular and germinal center B cells

.

Blood

.

2006

;

107

(

10

):

3967

-

3975

.

68.

Weller

Due south

,

Faili

A

,

Garcia

C

, et al.

CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans

.

Proc Natl Acad Sci USA

.

2001

;

98

(

iii

):

1166

-

1170

.

69.

William

J

,

Euler

C

,

Christensen

Southward

,

Shlomchik

MJ

.

Evolution of autoantibody responses via somatic hypermutation outside of germinal centers

.

Science

.

2002

;

297

(

5589

):

2066

-

2070

.

lxx.

Cerutti

A

,

Puga

I

,

Magri

G

.

The B cell helper side of neutrophils

.

J Leukoc Biol

.

2013

;

94

(

4

):

677

-

682

.

71.

Baumjohann

D

,

Preite

S

,

Reboldi

A

, et al.

Persistent antigen and germinal middle B cells sustain T follicular helper cell responses and phenotype

.

Immunity

.

2013

;

38

(

iii

):

596

-

605

.

72.

Pone

EJ

,

Zhang

J

,

Mai

T

, et al.

BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway

.

Nat Commun

.

2012

;

3

:

767

.

73.

Sciammas

R

,

Shaffer

AL

,

Schatz

JH

,

Zhao

H

,

Staudt

LM

,

Singh

H

.

Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma jail cell differentiation

.

Immunity

.

2006

;

25

(

2

):

225

-

236

.

74.

Pasqualucci

50

,

Guglielmino

R

,

Houldsworth

J

, et al.

Expression of the Aid protein in normal and neoplastic B cells

.

Blood

.

2004

;

104

(

ten

):

3318

-

3325

.

75.

Grumont

RJ

,

Gerondakis

Due south

.

Rel induces interferon regulatory cistron 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear gene kappaB

.

J Exp Med

.

2000

;

191

(

eight

):

1281

-

1292

.

76.

Calado

DP

,

Sasaki

Y

,

Godinho

SA

, et al.

The cell-bike regulator c-Myc is essential for the formation and maintenance of germinal centers

.

Nat Immunol

.

2012

;

13

(

11

):

1092

-

1100

.

77.

Kitano

M

,

Moriyama

South

,

Ando

Y

, et al.

Bcl6 protein expression shapes pre-germinal center B prison cell dynamics and follicular helper T cell heterogeneity

.

Immunity

.

2011

;

34

(

6

):

961

-

972

.

78.

Landgren

O

,

Staudt

L

.

MYD88 L265P somatic mutation in IgM MGUS

.

N Engl J Med

.

2012

;

367

(

23

):

2255

-

2256, NaN-2257

.

79.

Janz

Southward

.

Waldenström macroglobulinemia: clinical and immunological aspects, natural history, jail cell of origin, and emerging mouse models

.

ISRN Hematol

.

2013

;

2013

:

815325

.

eighty.

Ho

AW

,

Hatjiharissi

E

,

Ciccarelli

BT

, et al.

CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia

.

Blood

.

2008

;

112

(

12

):

4683

-

4689

.

81.

Castillo

JJ

,

Gustine

J

,

Meid

K

,

Dubeau

T

,

Hunter

ZR

,

Treon

SP

.

Histological transformation to lengthened big B-cell lymphoma in patients with Waldenström macroglobulinemia

.

Am J Hematol

.

2016

;

91

(

10

):

1032

-

1035

.

82.

Reynaud

CA

,

Descatoire

M

,

Dogan

I

,

Huetz

F

,

Weller

S

,

Weill

JC

.

IgM retention B cells: a mouse/human paradox

.

Prison cell Mol Life Sci

.

2012

;

69

(

10

):

1625

-

1634

.

83.

Rubtsov

AV

,

Rubtsova

Chiliad

,

Fischer

A

, et al.

Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c⁺ B-cell population is important for the development of autoimmunity

.

Blood

.

2011

;

118

(

v

):

1305

-

1315

.

84.

Hao

Y

,

O'Neill

P

,

Naradikian

MS

,

Scholz

JL

,

Cancro

MP

.

A B-jail cell subset uniquely responsive to innate stimuli accumulates in anile mice

.

Claret

.

2011

;

118

(

five

):

1294

-

1304

.

85.

Phalke

S

,

Marrack

P

.

Historic period (autoimmunity) associated B cells (ABCs) and their relatives

.

Curr Opin Immunol

.

2018

;

55

:

75

-

fourscore

.

86.

Lazarevic

V

,

Glimcher

LH

,

Lord

GM

.

T-bet: a bridge between innate and adaptive amnesty

.

Nat Rev Immunol

.

2013

;

13

(

11

):

777

-

789

.

87.

Kenderes

KJ

,

Levack

RC

,

Papillion

AM

,

Cabrera-Martinez

B

,

Dishaw

LM

,

Winslow

GM

.

T-Bet(+) IgM memory cells generate multi-lineage effector B cells

.

Cell Rep

.

2018

;

24

(

iv

):

824

-

837

.

88.

Cancro

MP

.

Age-associated B cells

.

Annu Rev Immunol

.

2020

;

38

(

1

):

315

-

340

.

89.

Rubtsova

K

,

Rubtsov

AV

,

van Dyk

LF

,

Kappler

JW

,

Marrack

P

.

T-box transcription factor T-bet, a key histrion in a unique type of B-cell activation essential for effective viral clearance

.

Proc Natl Acad Sci Usa

.

2013

;

110

(

34

):

E3216

-

E3224

.

90.

Tian

M

,

Hua

Z

,

Hong

S

, et al.

B cell-intrinsic MyD88 signaling promotes initial cell proliferation and differentiation to heighten the germinal center response to a virus-similar particle

.

J Immunol

.

2018

;

200

(

3

):

937

-

948

.

91.

Gupta

Chiliad

,

Han

JJ

,

Stenson

M

, et al.

Elevated serum IL-x levels in diffuse large B-prison cell lymphoma: a mechanism of abnormal JAK2 activation

.

Blood

.

2012

;

119

(

12

):

2844

-

2853

.

92.

Forrester

JV

,

McMenamin

PG

,

Dando

SJ

.

CNS infection and allowed privilege

.

Nat Rev Neurosci

.

2018

;

19

(

11

):

655

-

671

.

93.

Gravelle

P

,

Burroni

B

,

Péricart

S

, et al.

Mechanisms of PD-1/PD-L1 expression and prognostic relevance in non-Hodgkin lymphoma: a summary of immunohistochemical studies

.

Oncotarget

.

2017

;

8

(

27

):

44960

-

44975

.

94.

Cao

HY

,

Zou

P

,

Zhou

H

.

Genetic association of interleukin-10 promoter polymorphisms and susceptibility to diffuse big B-prison cell lymphoma: a meta-analysis

.

Gene

.

2013

;

519

(

two

):

288

-

294

.

95.

Iyer

SS

,

Cheng

G

.

Office of interleukin 10 transcriptional regulation in inflammation and autoimmune disease

.

Crit Rev Immunol

.

2012

;

32

(

1

):

23

-

63

.

96.

Coiffier

B

,

Thieblemont

C

,

Van Den Neste

E

, et al.

Long-term result of patients in the LNH-98.5 trial, the get-go randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte

.

Blood

.

2010

;

116

(

12

):

2040

-

2045

.

97.

Vitolo

U

,

Seymour

JF

,

Martelli

M

, et al;

ESMO Guidelines Commission

.

Extranodal diffuse large B-cell lymphoma (DLBCL) and principal mediastinal B-prison cell lymphoma: ESMO Clinical Exercise Guidelines for diagnosis, handling and follow-up

.

Ann Oncol

.

2016

;

27

(

suppl 5

):

v91

-

v102

.

98.

Nowakowski

GS

,

Feldman

T

,

Rimsza

LM

,

Westin

JR

,

Witzig

TE

,

Zinzani

PL

.

Integrating precision medicine through evaluation of cell of origin in treatment planning for diffuse large B-cell lymphoma

.

Blood Cancer J

.

2019

;

9

(

6

):

48

.

99.

Lionakis

MS

,

Dunleavy

M

,

Roschewski

M

, et al.

Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma

.

Cancer Cell

.

2017

;

31

(

6

):

833

-

843

.

100.

Grommes

C

,

Pastore

A

,

Palaskas

N

, et al.

Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma

.

Cancer Discov

.

2017

;

7

(

9

):

1018

-

1029

.

101.

Kelly

PN

,

Romero

DL

,

Yang

Y

, et al.

Selective interleukin-i receptor-associated kinase 4 inhibitors for the handling of autoimmune disorders and lymphoid malignancy

.

J Exp Med

.

2015

;

212

(

13

):

2189

-

2201

.

102.

Nagel

D

,

Bognar

M

,

Eitelhuber

Air-conditioning

,

Kutzner

G

,

Vincendeau

Yard

,

Krappmann

D

.

Combinatorial BTK and MALT1 inhibition augments killing of CD79 mutant diffuse large B cell lymphoma

.

Oncotarget

.

2015

;

half-dozen

(

39

):

42232

-

42242

.

103.

Fontán

L

,

Qiao

Q

,

Hatcher

JM

, et al.

Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth

.

J Clin Invest

.

2018

;

128

(

10

):

4397

-

4412

.

104.

Kapoor

I

,

Li

Y

,

Sharma

A

, et al.

Resistance to BTK inhibition by ibrutinib can exist overcome past preventing FOXO3a nuclear export and PI3K/AKT activation in B-cell lymphoid malignancies

.

Jail cell Death Dis

.

2019

;

x

(

12

):

924

.

105.

Stengel

KR

,

Bhaskara

S

,

Wang

J

, et al.

Histone deacetylase three controls a transcriptional network required for B cell maturation

.

Nucleic Acids Res

.

2019

;

47

(

20

):

10612

-

10627

.

106.

Jiang

Y

,

Ortega-Molina

A

,

Geng

H

, et al.

CREBBP inactivation promotes the development of HDAC3-dependent lymphomas

.

Cancer Discov

.

2017

;

seven

(

1

):

38

-

53

.

107.

Hatzi

K

,

Jiang

Y

,

Huang

C

, et al.

A hybrid machinery of action for BCL6 in B cells defined past formation of functionally distinct complexes at enhancers and promoters

.

Cell Rep

.

2013

;

4

(

iii

):

578

-

588

.

108.

Mondello

P

,

Tadros

S

,

Teater

Chiliad

, et al.

Selective inhibition of HDAC3 targets constructed vulnerabilities and activates allowed surveillance in lymphoma

.

Cancer Discov

.

2020

;

10

(

iii

):

440

-

459

.

109.

Takatsuka

S

,

Yamada

H

,

Haniuda

G

, et al.

IL-9 receptor signaling in retentivity B cells regulates humoral retrieve responses

.

Nat Immunol

.

2018

;

19

(

9

):

1025

-

1034

.

110.

Lv

X

,

Feng

L

,

Ge

10

,

Lu

K

,

Wang

X

.

Interleukin-9 promotes cell survival and drug resistance in diffuse large B-cell lymphoma

.

J Exp Clin Cancer Res

.

2016

;

35

(

1

):

106

.

Author notes

*

L.Five. and A.Chiliad.Thou. contributed equally to this study.

© 2020 past The American Club of Hematology

2020

Submit a comment

Name

Affiliations

Annotate title

Comment

You accept entered an invalid code

Cheers for submitting a comment on this article. Your annotate will exist reviewed and published at the journal's discretion. Please bank check for further notifications by email.

martinezpolday.blogspot.com

Source: https://ashpublications.org/blood/article/136/20/2263/463763/The-dangers-of-deja-vu-memory-B-cells-as-the-cells

Share this post