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Immunity Aug 2019Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the...
Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Cells, Cultured; Germinal Center; Humans; Immunoglobulin Class Switching; Mice; Mice, Inbred C57BL; Phylogeny; Plasma Cells; Plasmablastic Lymphoma; Receptors, Antigen, B-Cell; T-Lymphocytes, Helper-Inducer
PubMed: 31375460
DOI: 10.1016/j.immuni.2019.07.001 -
Haematologica Mar 2019IgG4-related disease is a fibro-inflammatory condition that can affect nearly any organ system. Common presentations include major salivary and lacrimal gland... (Review)
Review
IgG4-related disease is a fibro-inflammatory condition that can affect nearly any organ system. Common presentations include major salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. This review focuses on the hematologic manifestations of IgG4-related disease, including lymphadenopathy, eosinophilia, and polyclonal hypergammaglobulinemia. The disease can easily be missed by unsuspecting hematologists, as patients may present with clinical problems that mimic disorders such as multicentric Castleman disease, lymphoma, plasma cell neoplasms and hypereosinophilic syndromes. When IgG4-related disease is suspected, serum protein electrophoresis and IgG subclasses are helpful as initial tests but a firm histological diagnosis is essential both to confirm the diagnosis and to rule out mimickers. The central histopathological features are a dense, polyclonal, lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells (with an IgG4/IgG ratio >40%), storiform fibrosis, and obliterative phlebitis. Importantly for hematologists, the latter two features are seen in all tissues except bone marrow and lymph nodes, making these two sites suboptimal for histological confirmation. Many patients follow an indolent course and respond well to treatment, but a significant proportion may have highly morbid or fatal complications such as periaortitis, severe retroperitoneal fibrosis or pachymeningitis. Corticosteroids are effective but cause new or worsening diabetes in about 40% of patients. Initial response rates to rituximab are high but durable remissions are rare. More intensive lymphoma chemotherapy regimens may be required in rare cases of severe, refractory disease, and targeted therapy against plasmablasts, IgE and other disease biomarkers warrant further exploration.
Topics: Aged, 80 and over; Biomarkers; Biopsy; Combined Modality Therapy; Diagnosis, Differential; Diagnostic Imaging; Disease Management; Disease Susceptibility; Humans; Immunoglobulin G4-Related Disease; Male; Phenotype; Symptom Assessment; Treatment Outcome
PubMed: 30705099
DOI: 10.3324/haematol.2018.205526 -
Cell Discovery Jun 2023Understanding tumor heterogeneity and immune infiltrates within the tumor-immune microenvironment (TIME) is essential for the innovation of immunotherapies. Here,...
Understanding tumor heterogeneity and immune infiltrates within the tumor-immune microenvironment (TIME) is essential for the innovation of immunotherapies. Here, combining single-cell transcriptomics and chromatin accessibility sequencing, we profile the intratumor heterogeneity of malignant cells and immune properties of the TIME in primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) patients. We demonstrate diverse malignant programs related to tumor-promoting pathways, cell cycle and B-cell immune response. By integrating data from independent systemic DLBCL and follicular lymphoma cohorts, we reveal a prosurvival program with aberrantly elevated RNA splicing activity that is uniquely associated with PCNS DLBCL. Moreover, a plasmablast-like program that recurs across PCNS/activated B-cell DLBCL predicts a worse prognosis. In addition, clonally expanded CD8 T cells in PCNS DLBCL undergo a transition from a pre-exhaustion-like state to exhaustion, and exhibit higher exhaustion signature scores than systemic DLBCL. Thus, our study sheds light on potential reasons for the poor prognosis of PCNS DLBCL patients, which will facilitate the development of targeted therapy.
PubMed: 37308475
DOI: 10.1038/s41421-023-00559-7 -
Blood and Lymphatic Cancer : Targets... 2018Plasmablastic lymphoma (PbL) is a rare and aggressive B-cell malignancy with large neoplastic cells, most of them resembling plasmablasts that have a CD20-negative... (Review)
Review
Plasmablastic lymphoma (PbL) is a rare and aggressive B-cell malignancy with large neoplastic cells, most of them resembling plasmablasts that have a CD20-negative phenotype. Although initially described as being associated with HIV, over the years it has also been identified in patients with solid organ transplant and immunocompetent patients. Little is known about molecular basis that drives PbL, and still its diagnosis remains challenging given its rarity. However, proper recognition of its clinical characteristics, localization, and morphological features can establish a correct diagnosis of PbL within the spectrum of CD20-negative large B-cell lymphomas (LBCLs). PbL is characterized by CD20 and PAX5 negativity together with the expression of CD38, CD138, MUM1/IRF4, Blimp1, and XBP1 plasmacytic differentiation markers. It is usually associated with Epstein-Barr virus infections, and gene rearrangements. PbL should be carefully differentiated from other CD20-negative B-cell neoplasms, ie, primary effusion lymphoma, anaplastic lymphoma kinase-positive (ALK) large B-cell lymphoma, and LBCL in human herpesvirus 8-associated multicentric Castleman disease. Despite our improved understanding of this disease, its prognosis remains dismal with short overall survival. There is no standard of care for this entity. Several chemotherapy combinations have been used with hardly any differences on its outcome. Thus, new approaches with the addition of novel molecules are needed to overcome its poor prognosis. Our current understanding and knowledge of PbL relies primarily on case reports and small case series. In this review, we revise through an extensive literature search, the clinical and biological characteristics of this entity, and the potential therapeutic options.
PubMed: 31360094
DOI: 10.2147/BLCTT.S142814 -
Blood Cancer Discovery Jan 2023Genomic profiling revealed the identity of at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), including the MCD/C5 cluster characterized by aberrations in...
UNLABELLED
Genomic profiling revealed the identity of at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), including the MCD/C5 cluster characterized by aberrations in MYD88, BCL2, PRDM1, and/or SPIB. We generated mouse models harboring B cell-specific Prdm1 or Spib aberrations on the background of oncogenic Myd88 and Bcl2 lesions. We deployed whole-exome sequencing, transcriptome, flow-cytometry, and mass cytometry analyses to demonstrate that Prdm1- or Spib-altered lymphomas display molecular features consistent with prememory B cells and light-zone B cells, whereas lymphomas lacking these alterations were enriched for late light-zone and plasmablast-associated gene sets. Consistent with the phenotypic evidence for increased B cell receptor signaling activity in Prdm1-altered lymphomas, we demonstrate that combined BTK/BCL2 inhibition displays therapeutic activity in mice and in five of six relapsed/refractory DLBCL patients. Moreover, Prdm1-altered lymphomas were immunogenic upon transplantation into immuno-competent hosts, displayed an actionable PD-L1 surface expression, and were sensitive to antimurine-CD19-CAR-T cell therapy, in vivo.
SIGNIFICANCE
Relapsed/refractory DLBCL remains a major medical challenge, and most of these patients succumb to their disease. Here, we generated mouse models, faithfully recapitulating the biology of MYD88-driven human DLBCL. These models revealed robust preclinical activity of combined BTK/BCL2 inhibition. We confirmed activity of this regimen in pretreated non-GCB-DLBCL patients. See related commentary by Leveille et al., p. 8. This article is highlighted in the In This Issue feature, p. 1.
Topics: Humans; Mice; Animals; Myeloid Differentiation Factor 88; B-Lymphocytes; Lymphoma, Large B-Cell, Diffuse; Plasma Cells; Proto-Oncogene Proteins c-bcl-2
PubMed: 36346827
DOI: 10.1158/2643-3230.BCD-22-0007 -
PloS One 2021SLFN11 has recently been reported to execute cancer cells harboring replicative stress induced by DNA damaging agents. However, the roles of SLFN11 under physiological...
BACKGROUND
SLFN11 has recently been reported to execute cancer cells harboring replicative stress induced by DNA damaging agents. However, the roles of SLFN11 under physiological conditions remain poorly understood. Germinal center B-cells (GCBs) undergo somatic hypermutations and class-switch recombination, which can cause physiological genotoxic stress. Hence, we tested whether SLFN11 expression needs to be suppressed in GCBs during B-cell development.
OBJECTIVE
To clarify the expression profile of SLFN11 in different developmental stages of B-cells and B-cell-derived cancers.
METHODS
We analyzed the expression of SLFN11 by mining cell line databases for different stages of normal B-cells and various types of B-cell-derived cancer cell lines. We performed dual immunohistochemical staining for SLFN11 and B-cell specific markers in normal human lymphatic tissues. We tested the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on SLFN11 expression in GCB-derived lymphoma cell lines. We also examined the therapeutic efficacy of these drugs in combination with cytosine arabinoside and the effects of SLFN11 on the efficacy of cytosine arabinoside in SLFN11-overexpressing cells.
RESULTS
SLFN11 mRNA level was found low in both normal GCBs and GCB-DLBCL (GCB like-diffuse large B-cell lymphoma). Immunohistochemical staining showed low SLFN11 expression in GCBs and high SLFN11 expression in plasmablasts and plasmacytes. The EZH2 and HDAC epigenetic modifiers upregulated SLFN11 expression in GCB-derived lymphoma cells and made them more susceptible to cytosine arabinoside. SLFN11 overexpression further sensitized GCB-derived lymphoma cells to cytosine arabinoside.
CONCLUSIONS
The expression of SLFN11 is epigenetically suppressed in normal GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low SLFN11 expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside.
Topics: B-Lymphocytes; Cell Line, Tumor; Databases, Genetic; Epigenesis, Genetic; Epigenomics; Gene Expression; Gene Expression Regulation, Neoplastic; Germinal Center; Histone Deacetylase Inhibitors; Humans; Lymphocyte Activation; Lymphocytes; Lymphoma, Large B-Cell, Diffuse; Nuclear Proteins; Plasma Cells; Proto-Oncogene Proteins c-bcl-6
PubMed: 33513156
DOI: 10.1371/journal.pone.0237554 -
Scandinavian Journal of Immunology Sep 2020The maintenance of inner integrity of an organism is founded on the proper performance of two immunity branches, innate and adaptive immune responses. Recently, it... (Review)
Review
The maintenance of inner integrity of an organism is founded on the proper performance of two immunity branches, innate and adaptive immune responses. Recently, it became apparent that subset of splenic B cells named marginal zone B cells (MZB cells) exhibits unique developmental and functional features that bridge these two immunity branches. Strategically positioned at the site where blood and lymph are filtered, MZB cells represent a population of sentinels that rapidly proliferate and differentiate into IgM plasmablast cells when encountered with blood-borne, thymus-independent (TI) Ags. Moreover, MZB cells have intrinsic capability to induce potent CD4 helper T cell response and cytokine production upon stimulation with soluble antigens. Due to their ability to overcome a time gap prior the establishment of the full adaptive response towards pathogens, MZB cells connect and direct innate and adaptive immunity. An additional interesting characteristic of MZB cells is capacity to function as regulatory cells in autoimmune processes. MZB cells may also contribute to the control of autoimmunity via the induction of tolerance by apoptotic cells. Importantly, in the clear association with inflammation and autoimmunity, MZB cells may transform into MALT lymphoma, representing a concurrence point for the infection, immunity and malignancy. This paper presents an insight into the complex biology of marginal zone B cells and their role in intertwining and directing innate and adaptive immune processes at the physiological and pathological level.
Topics: Adaptive Immunity; Animals; B-Lymphocytes; Cellular Microenvironment; Disease Susceptibility; Homeostasis; Humans; Lymphocyte Activation; Spleen
PubMed: 32594535
DOI: 10.1111/sji.12920 -
Advances in Hematology 2015Plasmablastic lymphoma (PBL) is an aggressive subtype of non-Hodgkin's lymphoma (NHL), which frequently arises in the oral cavity of human immunodeficiency virus (HIV)... (Review)
Review
Plasmablastic lymphoma (PBL) is an aggressive subtype of non-Hodgkin's lymphoma (NHL), which frequently arises in the oral cavity of human immunodeficiency virus (HIV) infected patients. PBL shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts/plasmablasts, or with plasmacytic features and an immunophenotype of plasma cells. PBL remains a diagnostic challenge due to its peculiar morphology and an immunohistochemical profile similar to plasma cell myeloma (PCM). PBL is also a therapeutic challenge with a clinical course characterized by a high rate of relapse and death. There is no standard chemotherapy protocol for treatment of PBL. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine (CODOX-M/IVAC), or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) are possible options. Recently, a few studies have reported the potential value of the proteasome inhibitor bortezomib and thalidomide in PBL patients. The introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs) and CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials. The aim of this paper is to review the recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and outcome in patients with PBL.
PubMed: 26357515
DOI: 10.1155/2015/315289 -
JCI Insight Feb 2023To better characterize the heterogeneity of multiple myeloma (MM), we profiled plasma cells (PCs) and their B cell lymphopoiesis in the BM samples from patients with...
To better characterize the heterogeneity of multiple myeloma (MM), we profiled plasma cells (PCs) and their B cell lymphopoiesis in the BM samples from patients with monoclonal gammopathy of undetermined significance, smoldering MM, and active MM by mass cytometry (CyTOF) analysis. Characterization of intra- and interneoplastic heterogeneity of malignant plasmablasts and PCs revealed overexpression of the MM SET domain (MMSET), Notch-1, and CD47. Variations in upregulation of B cell signaling regulators (IFN regulatory factor 4 [IRF-4], CXCR4, B cell lymphoma 6 [Bcl-6], c-Myc, myeloid differentiation primary response protein 88 [MYD88], and spliced X box-binding protein 1 [sXBP-1]) and aberrant markers (CD319, CD269, CD200, CD117, CD56, and CD28) were associated with different clinical outcomes in clonal PC subsets. In addition, prognosis was related to heterogeneity in subclonal expression of stemness markers, including neuroepithelial stem cell protein (Nestin), SRY-box transcription factor 2 (Sox2), Krüppel-like factor 4 (KLF-4), and Nanog. Furthermore, we have defined significantly elevated levels of MMSET, MYD88, c-Myc, CD243, Notch-1, and CD47 from hematopoietic stem cells to PCs in myeloma B cell lymphopoiesis, noted even in premalignant conditions, with variably modulated expression of B cell development regulators, including IRF-4, Bcl-2, Bcl-6, and sXBP-1; aberrant PC markers (such as CD52, CD44, CD200, CD81, CD269, CD117, and CXCR4); and stemness-controlling regulators, including Nanog, KLF-4, octamer-binding transcription factor 3/4 (Oct3/4), Sox2, and retinoic acid receptor α2 (RARα2). This study provides the rationale for precise molecular profiling of patients with MM by CyTOF technology to define disease heterogeneity and prognosis.
Topics: Humans; Multiple Myeloma; CD47 Antigen; Myeloid Differentiation Factor 88; Lymphopoiesis; B-Lymphocytes
PubMed: 36752202
DOI: 10.1172/jci.insight.159924 -
Cancers Oct 2022Upregulated expression of the anti-apoptotic oncogene is a common feature of various types of B-cell malignancies, from lymphoma to leukemia or myeloma. It is currently...
Upregulated expression of the anti-apoptotic oncogene is a common feature of various types of B-cell malignancies, from lymphoma to leukemia or myeloma. It is currently unclear how the various patterns of deregulation observed in pathology eventually impact the phenotype of malignant B cells and their microenvironment. Follicular lymphoma (FL) is the most common non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells, and its major hallmark is the t(14:18) translocation occurring in B cell progenitors and placing the gene under the control of the immunoglobulin heavy chain locus regulatory region (IgH 3'RR), thus exposing it to constitutive expression and hypermutation. Translocation of onto Ig light chain genes, gene amplification, and other mechanisms yielding over-expression are, in contrast, rare in FL and rather promote other types of B-cell lymphoma, leukemia, or multiple myeloma. In order to assess the impact of distinct BCL2 deregulation patterns on B-cell fate, two mouse models were designed that associated and its full P1-P2 promoter region to either the IgH 3'RR, within a "3'RR-" transgene mimicking the situation seen in FL, or an Ig light chain locus context, through knock-in insertion at the Igκ locus ("Igκ-" model). While linkage to the IgH 3' RR mostly yielded expression in GC B-cells, the Igκ-driven up-regulation culminated in plasmablasts and plasma cells, boosting the plasma cell in-flow and the accumulation of long-lived plasma cells. These data demonstrate that the timing and level of BCL2 deregulation are crucial for the behavior of B cells inside GC, an observation that could strongly impact the lymphomagenesis process triggered by secondary genetic hits.
PubMed: 36358756
DOI: 10.3390/cancers14215337