Classical Hodgkin lymphoma (cHL) is unique among lymphoid malignancies in several key biological features. (i) The Hodgkin and Reed-Sternberg (HRS) tumor cells are rare among an extensive and complex ...microenvironment. (ii) They derive from B cells, but have largely lost the B-cell typical gene expression program. (iii) Their specific origin appears to be pre-apoptotic germinal center (GC) B cells. (iv) They consistently develop bi- or multinucleated Reed-Sternberg cells from mononuclear Hodgkin cells. (v) They show constitutive activation of numerous signaling pathways. Recent studies have begun to uncover the basis of these specific features of cHL: HRS cells actively orchestrate their complex microenvironment and attract many distinct subsets of immune cells into the affected tissues, to support their survival and proliferation, and to create an immunosuppressive environment. Reed-Sternberg cells are generated by incomplete cytokinesis and refusion of Hodgkin cells. Epstein-Barr virus (EBV) plays a major role in the rescue of crippled GC B cells from apoptosis and hence is a main player in early steps of lymphomagenesis of EBV
cHL cases. The analysis of the landscape of genetic lesions in HRS cells so far did not reveal any highly recurrent HRS cell-specific lesions, but major roles of genetic lesions in members of the NF-κB and JAK/STAT pathways and of factors of immune evasion. It is perhaps the combination of the genetic lesions and the peculiar cellular origin of HRS cells that are disease defining. A combination of such genetic lesions and multiple cellular interactions with cells in the microenvironment causes the constitutive activation of many signaling pathways, often interacting in complex fashions. In nodular lymphocyte predominant Hodgkin lymphoma, the GC B cell-derived tumor cells have largely retained their typical GC B-cell expression program and follicular microenvironment. For IgD-positive cases, bacterial antigen triggering has recently been implicated in early stages of its pathogenesis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Hodgkin's lymphoma was first described in 1832. The aetiology of this lymphoma, however, remained enigmatic for a long time. Only within the past 10 years has the B-cell nature of the pathognomonic ...Hodgkin and Reed-Sternberg (HRS) cells been revealed, along with several recurrent genetic lesions. The pathogenetic role for Epstein-Barr virus infection has also been substantiated. HRS cells in classical Hodgkin's lymphoma have several characteristics that are unusual for lymphoid tumour cells, and the Hodgkin's lymphoma microenvironment is dominated by an extensive mixed, potentially inflammatory cellular infiltrate. Understanding the contribution of all of these changes to the pathogenesis of this disease is essential for the development of novel therapies.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
The Hodgkin and Reed/Sternberg (HRS) tumor cells of classical Hodgkin lymphoma (HL) and the lymphocyte-predominant tumor cells of nodular lymphocyte–predominant HL are both derived from ...germinal center B cells. HRS cells, however, have largely lost their B-cell gene-expression program and coexpress genes typical of various types of hematopoietic cells. Multiple signaling pathways show a deregulated activity in HRS cells. The genetic lesions involved in the pathogenesis of HL are only partly known, but numerous members and regulators of the NF-κB and JAK/STAT signaling pathways are affected, suggesting an important role for these pathways in HL pathogenesis. Some genetic lesions involve epigenetic regulators, and there is emerging evidence that HRS cells have undergone extensive epigenetic alterations compared with normal B cells. HRS and lymphocyte-predominant cells are usually rare in the lymphoma tissue, and interactions with other cells in the microenvironment are likely critical for HL pathophysiology. T cells represent a main population of infiltrating cells, and it appears that HRS cells both inhibit cytotoxic T cells efficiently and also receive survival signals from Th cells in direct contact with them.
The development of follicular lymphoma (FL) from a founder B cell with an upregulation of B-cell lymphoma 2 (BCL2), via the t(14;18) translocation, to a proliferating clone, poised to undergo further ...transformation to an aggressive lymphoma, illustrates the opportunistic Darwinian process of tumorigenesis. Protection against apoptosis allows an innocent cell to persist and divide, with dangerous accumulation of further mutational changes, commonly involving inactivation of chromatin-modifying genes. But this is not all. FL cells reflect normal B cells in relying on expression of surface immunoglobulin. In doing so, they add another supportive mechanism by exploiting the natural process of somatic hypermutation of the IGV genes. Positive selection of motifs for addition of glycan into the antigen-binding sites of virtually all cases, and the placement of unusual mannoses in those sites, reveals a posttranslational strategy to engage the microenvironment. A bridge between mannosylated surface immunoglobulin of FL cells and macrophage-expressed dendritic cell–specific ICAM-3–grabbing nonintegrin produces a persistent low-level signal that appears essential for life in the hostile germinal center. Early-stage FL therefore requires a triad of changes: protection from apoptosis, mutations in chromatin modifiers, and an ability to interact with lectin-expressing macrophages. These changes are common and persistent. Genetic/epigenetic analysis is providing important data but investigation of the posttranslational landscape is the next challenge. We have one glimpse of its operation via the influence of added glycan on the B-cell receptor of FL. The consequential interaction with environmental lectins illustrates how posttranslational modifications can be exploited by tumor cells, and could lead to new approaches to therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hodgkin lymphoma (HL) is derived from mature B cells and subdivided into classical HL and nodular lymphocyte predominant HL (NLPHL). HL is unique among human B cell lymphomas because of the rarity of ...the lymphoma cells, the Hodgkin and Reed-Sternberg (HRS) cells in classical HL and the lymphocyte-predominant (LP) cells in NLPHL, which usually account for 0.1% to 10% of the cells in the affected tissues. Moreover, HRS cells are unique in the extent to which they have lost their B cell-typical gene expression pattern. Deregulation of transcription factor networks plays a key role in this reprogramming process. HRS cells show strong constitutive activity of the transcription factor NF-kappaB. Multiple mechanisms likely contribute to this deregulated activation, including signaling through particular receptors and genetic lesions. Inactivating mutations in the TNFAIP3 tumor suppressor gene, encoding a negative regulator of NF-kappaB activity, were recently identified in about 40% of patients with classical HL. HRS cells are latently infected by Epstein-Barr virus in about 40% of patients, and an important role of this virus in HL pathogenesis-in particular for cases in which HRS cells had lost the capacity to express a B-cell receptor due to destructive somatic mutation-was recently substantiated.
The origin of IgM(+)CD27(+) B lymphocytes with mutated IgV genes, which account for approximately 20% of human peripheral blood (PB) B cells, is controversially discussed. A generation in a primary ...diversification pathway, in T cell-independent immune responses, or in T cell-dependent germinal center (GC) reactions has been proposed. We show here that IgM(+)IgD(+)CD27(+) and IgM(+)IgD(-/low)CD27(+) B cell subsets carry, like class-switched memory B cells, mutations in the Bcl6 gene as a genetic trait of a GC experience. Moreover, the identification of PB IgM(+)IgD(+)CD27(+) B cells clonally related to GC-derived IgG(+) memory B cells with shared and distinct IgV gene mutations demonstrates the GC origin also of the former subset. These findings provide genetic evidence for a GC derivation of somatically mutated IgM(+) B cells and indicate that adult humans harbor a large population of IgM(+)IgD(+) post-GC memory B cells. Furthermore, the analysis revealed that a highly diverse and often very large population of memory B cells is generated from a given GC B cell clone, and that (preferentially IgM) memory B cells are generated already early in the GC reaction. This provides novel insights into the dynamics of GC reactions and the generation of a memory B cell repertoire.
Chromosomal translocations involving the immunoglobulin loci are a hallmark of many types of B-cell lymphoma. Other factors, however, also have important roles in the pathogenesis of B-cell ...malignancies. Most B-cell lymphomas depend on the expression of a B-cell receptor (BCR) for survival, and in several B-cell malignancies antigen activation of lymphoma cells through BCR signalling seems to be an important factor for lymphoma pathogenesis. Recent insights into the lymphomagenic role of factors supplied by the microenvironment also offer new therapeutic strategies.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific ...events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.
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IJS, NUK, SBMB, UL, UM, UPUK
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