Materiały źródłowe

• #1 Molecular biology of Hodgkin lymphoma | Leukemia

  https://www.nature.com/articles/s41375-021-01204-6

  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.

• #2 Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future

  https://www.mdpi.com/1422-0067/21/18/6623

  The MAPK/ERK pathway involves receptor-linked tyrosine kinases such as the epidermal growth factor receptor, which leads to activation of RAS, RAK, and MEK. […] Unique to HL, the malignant cells seen (H- and RS-cells) represent <5% of cells in the affected tissue. [...] The mechanisms by which H- and RS-cells attract such a diversity of accomplices is mediated through cytokine and growth factor release. [...] Immune tolerance is an important mechanism by which H- and RS-cells promote their own survival. [...] Despite these attempts to camouflage, cHL antigen presentation does occur. [...] The understanding of the importance of PD-L1 in this disease has led to the use of targeted PD-L1 inhibitors in cHL to enhance T-cell function. [...] Throughout this review, we have described multiple aspects of the tumorigenesis of classical Hodgkin lymphoma from the first genetic insults on healthy germinal center B-cells to their development into RS-cells through genetic instability orchestrated by telomeric dysfunction. [...] Nevertheless, the complete understanding of cHL remains challenging and will only be achieved through research focused on the early “dormant” lymphoid precursor and the complete molecular deciphering of its transition to H- and finally RS-cells.

• #3

  https://haematologica.org/article/view/4986

  Classical Hodgkins lymphoma (HL) is one of the most common human malignant lymphomas. […] The origin of HRS cells has, therefore, long been a matter of debate. With the description of clonally rearranged immunoglobulin (Ig) genes with a high frequency of somatic mutations it became clear that HRS cells are in most cases derived from germinal center (GC) or post-GC B cells. […] It is of particular interest to note that, despite their B-cell origin, HRS cells have, in most cases, lost the B-cell-specific gene expression program. […] Furthermore, it is unclear how such cells survive, as GC B cells with defective Ig production usually undergo apoptotic cell death. […] Despite great efforts and advances in the last years, the pathogenesis of HL has not been clarified. In particular, although at the genomic level several recurrent alterations have been described, no unifying genomic defect specific to the malignant HRS cells has yet been identified.

• #4 Classical Hodgkin lymphoma

  https://atlasgeneticsoncology.org/haematological/1569/classical-hodgkin-lymphoma

  Hodgkin lymphoma (HL) was one of the earliest cancers to be cured with multiagent chemotherapy even before its biology was understood. […] Hodgkin and Reed-Sternberg (HRS) cells, the tumour cells of cHL, derive from preapoptotic crippled germinal center (GC) B cells. In fact, molecular features of HRS cells in cHL demonstrate that they are derived from GC B cells that have acquired disadvantageous immunoglobulin variable chain gene mutations and normally would have undergone apoptosis. […] Recurrent genetic alterations have been identified in HRS cells of cHL. These lesions affecting members of the NF-kappaB or JAK/STAT signalling pathways include inactivating mutation in NFKBIA (10-20% of cases), NFKBIE (10%), TNFAIP3 (40%), SOCS1 (40%), genomic gains of RELA (30%) and JAK2 (30%) and rare BCL3 translocations. […] Interestingly, HRS cells show aberrant somatic hypermutation of several proto-oncogenes (PIM1, RHOH (TTF), MYC, PAX5) in a considerable fraction of cases.

• #5

  https://omim.org/entry/236000

  A link between Hodgkin disease and Epstein Barr virus (EBV) was first hinted at through epidemiologic studies (Munoz et al., 1978; Mueller et al., 1989). […] A possible role for EBV in the pathogenesis of Hodgkin disease was suggested by direct detection of EBV DNA in tumor biopsies in up to 50% of Hodgkin disease cases (Weiss et al. (1987, 1989); Wu et al., 1990) and the finding of a consistent pattern of EBV latent gene transcription in EBV-positive Reed-Sternberg cells (Pallesen et al., 1991; Deacon et al., 1993), as demonstrated by in situ hybridization. […] As reviewed by Ambinder (2003), refinements in molecular techniques remove all doubts about the origin and character of the Reed-Sternberg cells in classic Hodgkin disease: they are neoplastic cells of B cell lineage. […] They differ from most other B cell-lineage lymphomas in that, although they carry immunoglobulin genes that have undergone the rearrangements that should allow them to produce immunoglobulins, they do not express or produce immunoglobulins.

• #6 Pathology Outlines – Classic Hodgkin lymphoma

  https://www.pathologyoutlines.com/topic/lymphomanonBclassic.html

  Classic Hodgkin lymphoma (CHL): B cell derived lymphoma characterized by distinctive immunophenotype and relatively few malignant cells in a nonneoplastic inflammatory background. […] 4 subgroups (nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depleted) with distinct clinical, morphologic and epidemiologic characteristics. […] Multiple mechanisms to evade immunosurveillance, including upregulation of programmed death ligand 1 / programmed death ligand 2 (PDL1 / PDL2). […] Pathophysiology is not completely understood. […] Malignant Reed-Sternberg cells derived from preapoptotic germinal center B cells with a disrupted B cell program. […] In a subset of cases, IgVH mutations lead to dysfunctional / absent B cell receptor, prohibiting antigenic selection; incompatible with survival of normal B cells.

• #7 Pathophysiology of Hodgkin’s Lymphoma and Role of Immune System

  https://www.fortunejournals.com/articles/pathophysiology-of-hodgkinrsquos-lymphoma-and-role-of-immune-system.html

  Two Main components of Hodgkin lymphoma are first one is Hodgkin and Reed Sternberg cells HRS and the second one is lymphoma predominant HP cells. Cellular origins of Hodgkin Reed-Sternberg cells were not clear for many years. The reason the HRS cells have phenotype in immunological aspects that did not match with the phenotype of any normal cell of immune system. […] The steps included in the process in which transfer of malignant GC B cells (pre apoptotic) to the HRS cells is not known properly however, get away from caspase-mediated cell death appears to be the initial and important step. […] In HRS Cells, the B cell down regulation process is not clearly known. Although the quantity of those factors that are taking part is clear. This incorporates down regulation of transcription element for the genes of B-cell (such as OCT2, PU.1, BOB1), up regulation of transcription element which represses the appearance of B-cell (such as ID2, ABF1), and genetic quieting of the genes of B-cell.

• #8

  https://www.jci.org/articles/view/61245

  In about 40% of classical HL in the Western world, and in more than 90% of pediatric cases of HL in Central America, HRS cells are latently infected by EBV, a -herpes virus. HRS cells are clonally infected, suggesting that EBV infection is an early event in HL pathogenesis. EBV has several types of latency, and in HRS cells latency II is observed, meaning that EBV-encoded genes EBV nuclear antigen 1 (EBNA1), latent membrane protein 1 (LMP1), and LMP2a are expressed. EBNA1 is essential for the replication of the episomal EBV genome in proliferating cells. LMP1 mimics an active CD40 receptor, a central costimulatory molecule for B cells. LMP2a carries a cytoplasmic motif that resembles the signaling module of the BCR. As CD40 and BCR signaling are main regulators of survival and selection of GC B cells, it was speculated that LMP1 and LMP2a can rescue BCR-deficient B cells from apoptosis by replacing these signals.

• #9 The contribution of ebv to the pathogenesis of classical hodgkin lymphoma – Vrzalikova – Annals of Lymphoma

  https://aol.amegroups.org/article/view/7322/html

  The oncogenic Epstein-Barr virus (EBV) is present in a subset of cases of classical Hodgkin lymphoma (cHL). […] We believe it is now timely to revisit the contribution of EBV to the pathogenesis of cHL, particularly with respect to the role of the viral latent genes, some of which are now being explored as targets of new drug and immunotherapeutic approaches. […] EBV was initially suggested to be involved in the pathogenesis of cHL after it was shown that patients had raised antibody levels to EBV antigens in their blood. […] An aetiological role for EBV in cHL was supported by the detection of viral genomes bearing identical fusion sequences in biopsies. […] EBV is consistently retained during disease progression, suggesting it is required for maintenance of the tumour phenotype. […] EBV is associated with cHL, but not with NLPHL. […] The incidence of EBV-positive cHL is also more common in HIV-positive individuals especially when the levels of immune impairment are at intermediate levels. […] A prior history of infectious mononucleosis (IM) is associated with an increased risk of developing EBV-positive, but not EBV-negative, cHL.

• #10 Hodgkin Lymphoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499969/

  Hodgkin lymphoma (HL) is a rare monoclonal lymphoid neoplasm characterized by the following four features: HL usually presents in young adults, commonly arises in cervical lymph nodes, involves scattered large mononuclear Hodgkin and multinucleated Reed-Sternberg cells on a background of non-neoplastic inflammatory cells, and characteristic neoplastic cells are often surrounded by T lymphocytes. […] Hodgkin lymphoma generally has an excellent prognosis, though this depends on several factors. […] The exact etiology of Hodgkin lymphoma is unknown. However, there is an increased risk of Hodgkin lymphoma in Epstein-Barr (EBV) and Human immunodeficiency virus (HIV) infections, autoimmune diseases, and immunosuppression. […] EBV has been found to be more common in the mixed cellularity and lymphocyte-depleted subtypes of Hodgkin lymphoma. Loss of immune surveillance has been proposed as the possible disease etiology in EBV-positive disease.

• #11 The contribution of ebv to the pathogenesis of classical hodgkin lymphoma – Vrzalikova – Annals of Lymphoma

  https://aol.amegroups.org/article/view/7322/html

  EBV-infected HRS cells express a restricted pattern of virus latency characterised by the presence of EBVs maintenance protein, EBNA1, as well as both latent membrane proteins. […] While the contribution of the EBV latent proteins to the pathogenesis of cHL is increasingly better understood, the roles of the EBV miRNAs have only just begun to be explored. […] EBNA1 is essential for the maintenance of EBV episomes in infected cells, as it is a key viral replication factor and is responsible for tethering viral genomes to the chromosomes of the host cell; loss of EBNA1 expression therefore results in the loss of EBV genomes during cell division. […] EBNA1 inhibits TGF signalling, in part by modulating the levels of SMAD2. […] LMP1 is a constitutively active homologue of CD40 that has been shown to activate NF-B, JAK/STAT, AP-1 and phosphatidylinositol-3 kinase (PI3K)/AKT signalling. […] The requirement for more genetic changes in EBV-negative cHL is supported by other studies which show that EBV-positive cHL has significantly fewer chromosome abnormalities than EBV-negative cHL.

• #12 Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future

  https://www.mdpi.com/1422-0067/21/18/6623

  Our understanding of the tumorigenesis of classical Hodgkin lymphoma (cHL) and the formation of Reed–Sternberg cells (RS-cells) has evolved drastically in the last decades. […] However, important gaps in knowledge remain that may hold the key for significant changes of paradigm in this lymphoma. […] The development of malignant H- and RS-cells can be traced down to early events that trigger healthy germinal center B cells to transform step by step into neoplastic cells. […] The association between EBV and cHL and its role in tumorigenesis is well demonstrated. […] The underlying mechanism by which EBV acts as an oncogene in cHL is thought to arise from the expression of EBER1, EBER2, EBNA1, LMP1, LMP2A, and LMP2B (latency type II) seen in EBV positive H- and RS-cells. […] LMP1 is a multifunctional oncoprotein known to cause constitutive activation of the NF-kB pathway, which leads to inhibition of apoptosis and provides the cells other survival benefits.

• #13 Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7554683/

  Our understanding of the tumorigenesis of classical Hodgkin lymphoma (cHL) and the formation of Reed-Sternberg cells (RS-cells) has evolved drastically in the last decades. […] However, important gaps in knowledge remain that may hold the key for significant changes of paradigm in this lymphoma. […] The association between EBV and cHL and its role in tumorigenesis is well demonstrated. […] The underlying mechanism by which EBV acts as an oncogene in cHL is thought to arise from the expression of EBER1, EBER2, EBNA1, LMP1, LMP2A, and LMP2B (latency type II) seen in EBV positive H- and RS-cells. […] LMP1 is a multifunctional oncoprotein known to cause constitutive activation of the NF-kB pathway, which leads to inhibition of apoptosis and provides the cells other survival benefits. […] The current scenarios are reviewed and include i) the impact of telomere dysfunction on genetic instability in cHL, ii) the constitutional activation of anti-apoptotic cellular pathways, iii) the role of the tumoral microenvironment, and iv) the mechanisms of immune evasion.

• #14 Molecular biology of Hodgkin lymphoma | Leukemia

  https://www.nature.com/articles/s41375-021-01204-6

  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 sequence of events during malignant transformation of pre-apoptotic GC B cells toward HRS cells is poorly understood, but escape from programmed cell death seems to be an early and essential event. […] In this regard, it is an intriguing observation that all cases with crippling mutations that prevent expression of a BCR were found to be Epstein-Barr virus (EBV) positive. […] The mechanisms for the downregulation of B-cell program in HRS cells are not well understood, but a number of contributing factors are known. […] A direct role of antigen triggering in the pathogenesis of NLPHL is supported by the finding that in IgD-expressing LP cells, the BCR frequently binds to a Moraxella catarrhalis-derived antigen and the M. catarrhalis encoded IgD-binding superantigen MID/hag, causing an unusual combined antigenic and superantigenic triggering of the BCR of LP cells.

• #15 The contribution of ebv to the pathogenesis of classical hodgkin lymphoma – Vrzalikova – Annals of Lymphoma

  https://aol.amegroups.org/article/view/7322/html

  EBV appears to be crucial for the survival of HRS progenitors harbouring so called crippling mutations in immunoglobulin genes; these mutations are found almost exclusively in EBV positive cases. […] LMP2A also contributes to the transcriptional programme of cHL, for example by reducing the expression of numerous B cell transcription factors, including EBF1 and E2A. […] The TME is a defining feature of cHL and there is some evidence that EBV is at least partly responsible for reshaping this TME through expression of the latent genes, and also potentially through limited induction of the lytic cycle. […] The function of EBV-specific T cells in the TME of cHL might be compromised by a variety of immune evasion mechanisms. […] A subset of cHL patients harbor EBV in their tumour cells. […] Notwithstanding debate over EBVs exact contribution to the oncogenic process in cHL, there is undoubtedly an opportunity to exploit the presence of EBV in tumours for patient benefit.

• #16

  https://haematologica.org/article/view/4986

  The deregulation of these signaling pathways is found in the vast majority or even all HRS cells of nearly all HL cases analyzed, pointing to the central relevance of these pathways for HRS cell survival, growth and regulation of HRS cell-specific gene expression. […] The simultaneous constitutive activation of all these signaling pathways is unique to HL and reveals that HRS cells require strong cell-autonomous signals ensuring growth and apoptosis protection. […] Up to now, no single unifying genomic defect has been described for HRS cells. […] The available data point to an unusual complex karyotype of the HRS cells with ongoing rearrangement activity. […] In summary, analyses of genomic alterations in HRS cells have confirmed the significance of deregulated signaling pathways identified by molecular biology approaches.

• #17 Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future

  https://www.mdpi.com/1422-0067/21/18/6623

  The current scenarios are reviewed and include i) the impact of telomere dysfunction on genetic instability in cHL, ii) the constitutional activation of anti-apoptotic cellular pathways, iii) the role of the tumoral microenvironment, and iv) the mechanisms of immune evasion. […] The NF-kB family, composed of Rel-A, Rel-B, cRel, p50, and p52, is a group of cytoplasmic proteins that translocate to the nucleus and act as transcription factors for proteins involved in inflammatory and anti-apoptotic signaling cascades. […] The activation of NF-kB is restricted by NF-kB inhibitors, which undergo ubiquitination and degradation upon activation of specific kinases. […] Many mechanisms have been demonstrated to lead to NF-kB constitutional activation in Hodgkin lymphoma. […] The JAK-STAT signaling pathway requires activation of the JAK tyrosine kinases, which include JAK1, JAK2, JAK3, and TYK2 on the inner side of the cytoplasmic membrane.

• #18 Hodgkin’s lymphoma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Hodgkin%27s_lymphoma_pathophysiology

  Hodgkin’s lymphoma is a potentially curable cancer, in which malignancy originates from lymphocytes. Hodgkin lymphoma is characterized by the presence of multinucleated giant cells Reed-Sternberg cells, derived from germinal center or postgerminal center B cells. In all four subtypes of classic Hodgkin lymphoma the Reed-Sternberg cells have a similar immunophenotype. Whereas in the NLPHL the Reed-Sternberg cells have a distinctive B-cell immunophenotype. […] Most Reed-Sternberg cells are of B-cell origin, derived from lymph node germinal centers. Molecular analysis of single isolated Reed-Sternberg cells and variants has been determined the origin of the neoplastic Reed-Sternberg cells. Despite having the genetic signature of a B cell, the Reed-Sternberg cells of classical HL fail to express most B-cell specific genes, including the Ig genes and no longer able to produce antibodies. The Ig genes of Reed-Sternberg cells have undergone both V(D)J rearrangements and somatic hypermutation. Growth and survival of classic RS cells are dependent to the activation of the nuclear factor kappa B (NF-kB) transcription factor-signaling pathway. This activation can occur by several mechanisms: NF-B may be activated either by EBV infection or by some other mechanism and turns on genes that promote lymphocyte survival and proliferation. The constitutive nuclear activity of NF-kB can both prevent apoptosis and promote cell proliferation. EBV+ tumor cells express viral latent membrane protein-1 (LMP-1), a protein encoded by the EBV genome that transmits signals leads to NF-kB activation. NF-kB is degraded normally by the „I kappa B (IkB)” family in order to prevent the unwanted stimulation and neoplasm formation. However, there are specific cellular proteins which lead to inactivation of the (IkB). So, by inactivating the (IkB), the NF-kB transcription factors will not be degraded and leads to gene transcriptions activation. In Hodgkin’s lymphoma, there are elevated levels of the NF-kB proteins especially c-REL and REL-A. Unstopped activation of (NF-kB): Active (NF-kB) will lead to constituent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells. Activation of (NF-kB) occurs due to the following causes: Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB, Alteration in the NF-kB itself protecting it from inhibition by IkB, Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB. NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following: (ICAM-1) gene, GM-CSF gene, IL-6 gene, IKBA gene. Besides NF-kB signaling pathway, Hodgkin’s lymphoma can be caused by mutations in JAK-STAT pathway. Alterations in JAK tyrosine kinases signaling lead to high levels of activated STAT pathway which is considered an observed feature in some cases of HL.

• #19 Hodgkin lymphoma

  https://atlasgeneticsoncology.org/haematological/2068/hodgkin-lymphoma

  Hodgkin lymphoma (HL) involves a clonal expansion of neoplastic B lymphocytes. A very small subset of cases of classical HL may derive from T cells. […] Several recurrent genetic lesions have been identified in HRS cells of classical HL. The most frequently found lesions affect members of the NF-kappaB or JAK/STAT signaling pathways: inactivating mutation in NFKBIA (10-20% of cases), NFKBIE (ca. 10% of cases), TNFAIP3 (40%), SOCS1 (40%), genomic gains of REL (30%) and JAK2 (30%) and rare BCL3 translocations. TNFAIP3 mutations are mainly found in Epstein-Barr virus-negative cases of HL, suggesting that TNFAIP3 mutations and EBV infection are alternative pathogenetic mechanisms in HL. […] Few genetic lesions are known for LP cells of lymphocyte predominant HL: mutations in SOCS1 and translocations involving the BCL6 protooncogene. Mutations in TNFAIP3 or NFKBIA seem to play no role in LP cells, although they also show strong NF-kappaB activity.

• #20 Pathology Outlines – Classic Hodgkin lymphoma

  https://www.pathologyoutlines.com/topic/lymphomanonBclassic.html

  HIV infection. […] Family history of CHL, particularly siblings. […] Hodgkin and Reed-Sternberg cells show numerical chromosome abnormalities in almost all cases. […] 90% of CHL shows copy number gain or amplification at 9p24.1; causes increased expression of PDL1 and PDL2. […] Gene mutations in components of the JAK / STAT and NFkB signaling pathways promote cell proliferation and survival.

• #21 Molecular biology of Hodgkin lymphoma | Leukemia

  https://www.nature.com/articles/s41375-021-01204-6

  A particular genetic feature of cHL is that a fraction of the lymphoma clone (the Reed-Sternberg cells) is bi- or multinucleated. […] The causes for the consistent appearance of bi-/multinucleated cells in HL are not understood, but a downregulation of key factors of the cytokinesis process may contribute to this. […] A main finding from numerous studies is that mutations in members of the NF-B pathway are a main feature of HRS cells. […] The JAK/STAT signaling pathway, which is constitutively active in HRS cells and represents the main mediator of cytokine signaling, is a second pathway that shows recurrently mutated genes in various of its members in HRS cells. […] HRS cells produce a plethora of cytokines, chemokines, and interleukins apart from several growth and stimulating factors, so their secretion supports the recruitment of different subtypes of immune cells into the tissue.

• #22 Pathology Outlines – Classic Hodgkin lymphoma

  https://www.pathologyoutlines.com/topic/lymphomanonBclassic.html

  Postulated to circumvent apoptosis by differentiating toward distinct subset of CD30+ post germinal center memory B cells. […] Cell proliferation and survival promoted by alterations in signaling pathways, including JAK / STAT, NFkB, PI3K / AKT and MAPK / ERK. […] EBV infection thought to drive aberrant signaling in EBV+ cases. […] Reed-Sternberg cell evasion of immunosurveillance: Increased programmed death ligand 1 / programmed death ligand 2 (PDL1 / PDL2) expression. […] Downregulation of MHC I / MHC II expression. […] Secretion of immunosuppressive cytokines. […] Infection (EBV, human immunodeficiency virus [HIV]) is thought to facilitate in a subset of cases. […] Factors associated with increased risk of developing CHL: EBV positive CHL: prior infectious mononucleosis, HLA-A*01 allele.

• #23 Hodgkin Lymphoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499969/

  Hodgkin lymphoma has unique neoplastic cells in both the classical and NLP-HL types. Reed-Sternberg (RS) cell is a neoplastic, large multinucleated cell with two mirror-image nuclei (owl eyes) within a reactive cellular background. […] The RS cell is usually aneuploid with no consistent cytogenetic abnormality. […] On the other hand, NLP-HL lacks the typical RS cells but has lymphocytic and histiocytic cells, which are characterized by larger cells with folded multilobulated nuclei (also known as popcorn cells or LP cells). […] Morphology is used to determine Hodgkin lymphoma variants and NLP-HL. […] In conclusion, morphology and immunophenotype of both the neoplastic cells and the background infiltrate are crucial in diagnosing HL and its different subtypes. […] Each subtype of Hodgkin lymphoma has distinct clinical features.

• #24 Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7554683/

  Three pathways, NF-kB, JAK-STAT, and MAPK/ERK, were shown to be activated in H- and RS-cells and involved in increased tumor cell survival. […] The involvement of the NF-kB pathway in tumorigenesis is well documented. […] Put together, there is growing evidence to support the fact that anti-apoptotic signaling pathways are constitutively activated in both EBV positive and negative cHL as a result of intrinsic mutations of key regulators of the pathway and from constant activation of its receptors from the tumoral microenvironment. […] The mechanisms by which H- and RS-cells attract such a diversity of accomplices is mediated through cytokine and growth factor release. […] The complex intricacies of the tumoral microenvironment go beyond the scope of this paper and have been comprehensively reviewed.

• #25 Molecular biology of Hodgkin lymphoma | Leukemia

  https://www.nature.com/articles/s41375-021-01204-6

  Taken together, HRS cells are characterized by the deregulated and partly aberrant constitutive activation of multiple signaling pathways and transcription factors. […] The extensive remodeling of the lymphoma microenvironment in cHL has most likely two main pathobiological functions, namely first to attract immune cells that support the survival and proliferation of HRS cells, and second to generate a microenvironment in which HRS cells can escape from anti-tumor immune control. […] HRS cells utilize a multitude of factors that contribute to immune evasion. […] The lack of MHC class I expression is often due to inactivating mutations in the B2M gene. […] Taken together, cHL shows a unique remodeling of the lymph node microenvironment, which is orchestrated by the HRS cells through secretion of numerous cytokines and chemokines.

• #26 Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7554683/

  Immune tolerance is an important mechanism by which H- and RS-cells promote their own survival. […] Despite these attempts to camouflage, cHL antigen presentation does occur. […] The understanding of the importance of PD-L1 in this disease has led to the use of targeted PD-L1 inhibitors in cHL to enhance T-cell function. […] Throughout this review, we have described multiple aspects of the tumorigenesis of classical Hodgkin lymphoma from the first genetic insults on healthy germinal center B-cells to their development into RS-cells through genetic instability orchestrated by telomeric dysfunction. […] We have also discussed the multiple ways by which H- and RS-cells ensure their survival with the help of a selective recruitment of cells in their microenvironment, the constitutional activation of anti-apoptotic pathways, and elaborate host-immune system evasion.

• #27

  https://www.jci.org/articles/view/61245

  The genomic region on chromosome 9p24, which shows gains in HRS cells and in which the JAK2 gene is located, also encompasses the gene JMJD2C and the programmed death 1 ligand (PD-1L) genes PD-L1 and PD-L2. PD-1Ls can inhibit PD-1expressing T cells and thereby may contribute to an immunosuppressive microenvironment in HL.

• #28 Pathophysiology of Hodgkin’s Lymphoma and Role of Immune System

  https://www.fortunejournals.com/articles/pathophysiology-of-hodgkinrsquos-lymphoma-and-role-of-immune-system.html

  All the patients throughout the world exhibit a defect in their cellular immunity persistently when suffer with this disease. […] EBV stands for Epstein-Barr virus which is the main irresistible entity that is related with Hodgkin’s disease. In about 40% of cases, Hodgkin and Reed Sternberg cells were found to have RNA encoded by Epstein-Barr. […] The Epstein-Barr virusal gene expression of Epstein-Barr nuclear antigen 1 (EBNA-1), latent membrane protein 1 (LMP1) and latent membrane protein 2 (LMP2) – (type II inactivity) is the sign of EBV-positive Hodgkin’s disease. […] The tumor cells secrete cytokine and chemokine and contribute its part to get away from the immune system. […] The activation of Fas/FasL pathway leads to the fact that those tumors that express this FasL can easily avoid the host’s immunity. […] One more way by which malignant cells can avoid immune response is by the production of PGE2 and IDO.

• #29

  https://haematologica.org/article/view/4986

  In summary, genomic studies of HRS cells have advanced our understanding of HL tumor biology by revealing a number of genetic defects with pathogenetic relevance, such as amplifications of genes encoding components of disease-associated signaling cascades and transcription factor networks. However, no recurrent HRS cell-characteristic genetic lesion has so far been identified. […] The challenge for future work will be to integrate the results obtained by genetic and molecular biology approaches into a common pathogenetic concept, and to identify the unifying molecular defects of classical Hodgkins lymphoma.

• #30 SciELO Brazil – CD20 role in pathophysiology of Hodgkin’s disease CD20 role in pathophysiology of Hodgkin’s disease

  https://www.scielo.br/j/ramb/a/Fvzwwj55rdGqTPwwLXkSZTF/

  CD20 seems to be a marker for HRS cell origin and has a key importance in: suppression of Th1 antitumoral immune responses through IL-10 production; stimulation of non-malignant B lymphocytes through cytokine liberation, which supports HRS cell survival; proliferation of HRS cells by direct stimuli on Hodgkin stem cells. […] Anti-CD20 therapy is a great modality of treatment, because of its potential to inhibit different stages in the physiopathogenesis of Hodgkins disease. […] In early stages, gold standard therapies (chemo and radiotherapy), not combined with mAb, yield good results, except for LPHL, in which massive CD20 expression has a powerful response to mAb drugs even as monotherapy. […] As a prognostic factor, CD20 expression is still controversial, but most studies have pointed out evidence that it could positively affect disease outcomes, and association between classic chemotherapy regimen and mAb drugs, especially rituximab, may improve overall survival and failure-free survival.

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