Materiały źródłowe

• #1 Lymphoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560826/

  Lymphoma comprises heterogeneous malignancies that arise from the clonal proliferation of lymphocytes. […] Lymphomas are a heterogeneous group of malignancies that arise from the clonal proliferation of B- cell, T- cell and natural killer (NK) cell subsets of lymphocytes at different stages of maturation. […] Different environmental, infectious, and genetic factors have been identified, which predispose to lymphoma. […] Chronic stimulation of lymphoid tissue also increases the risk of lymphoma development. Persistent infection with viruses like Epstein Barr virus and cytomegalovirus also predisposes to the development of lymphoma. […] Different stressors in the form of infectious, inflammatory, and toxic factors interact with the genetic makeup of the human host in a complex manner to result in lymphomagenesis.

• #1 Pathobiology of follicular lymphoma – UpToDate

  https://www.uptodate.com/contents/pathobiology-of-follicular-lymphoma

  Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma. […] The molecular pathogenesis of FL is a complex, multistep process during which a single follicular B cell acquires all of the genetic and epigenetic alterations needed for malignant transformation. […] The development of the majority of FL tumors in adults is dependent on the overexpression of B cell leukemia/lymphoma 2 (BCL-2) located on chromosome band 18q21. BCL-2 is an oncogene that blocks programmed cell death (apoptosis). As such, overexpression results in increased cell survival. BCL-2 overexpression in itself is not sufficient for FL development and other genetic lesions or host factors are required.

• #1 Mechanisms of B-cell lymphoma pathogenesis | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1589

  A hallmark of many types of B-cell lymphoma is reciprocal chromosomal translocations involving one of the immunoglobulin loci and a proto-oncogene. As a consequence of such translocations, the oncogene comes under the control of an active immunoglobulin locus, causing deregulated, constitutive expression of the translocated gene. […] 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. […] The recognition that the survival and/or proliferation of many B-cell lymphomas depends on their interaction with other cells in the microenvironment, as well as on expression of the B-cell receptor and, sometimes, antigen activation, might lead to novel treatment options for B-cell lymphomas.

• #1

  https://www.jci.org/articles/view/63186/citations

  The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program. […] Most tumors are characterized by recurrent secondary genetic alterations including genomic gains, losses, and mutations, some providing a growth advantage, including alterations in MLL2, EPHA7, TNFRSF14, and EZH2. […] Lastly, crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation.

• #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. […] 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. […] 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.

• #1 Molecular Pathogenesis of Follicular Lymphoma: From Genetics to Clinical Practice

  https://www.mdpi.com/2673-6357/3/4/41

  Follicular lymphoma (FL), a generally indolent disease that derives from germinal center (GC) B cells, represents around 20–25% of all new lymphomas diagnosed in Western countries. The characteristic t(14;18)(q32;q21) translocation that places the BCL2 oncogene under control of the immunoglobulin heavy-chain enhancer occurs in pro- or pre-B cells. However, additional secondary alterations are required for the development of overt FL, which mainly affects genes involved in epigenetic and transcriptional regulation, signaling and B cell differentiation, the BCR/NF-κB pathway, and proliferation/apoptosis. […] New insights into the FL pathogenesis suggest that FL lacking the BCL2 translocation might be a distinct biological entity with genomic features different from the classical FL. […] Although FL is considered an indolent disease, around 10–20% of cases eventually transform to an aggressive lymphoma, usually a diffuse large B cell lymphoma, generally by a divergent evolution process from a common altered precursor cell acquiring genomic alterations involved in the cell cycle and DNA damage responses.

• #1 An update on Burkitt lymphoma: a review of pathogenesis and multimodality imaging assessment of disease presentation, treatment response, and recurrence | Insights into Imaging | Full Text

  https://insightsimaging.springeropen.com/articles/10.1186/s13244-019-0733-7

  Burkitt lymphoma (BL) is a highly aggressive, rapidly growing B cell non-Hodgkin lymphoma, which manifests in several subtypes including sporadic, endemic, and immunodeficiency-associated forms. Pathologically, BL is classically characterized by translocations of chromosomes 8 and 14 resulting in upregulation of the c-myc protein transcription factor with upregulation of cell proliferation. […] BL development depends on expression of MYC gene, which encodes for the c-myc protein transcription factor, which is located on chromosome 8q24 and regulates cell proliferation, differentiation, and apoptosis. BL is characterized by inappropriately high levels of c-myc, which can result via several different mechanisms, most commonly by translocation of the long arm of chromosome 8 (containing the MYC gene) and the Ig heavy chain gene on chromosome 14. c-Myc overexpression leads to rapid B cell proliferation accounting for the rapid doubling time of BL tumor cells (between 24 and 48 h).

• #1 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

  Hodgkin’s lymphoma is a disease which originates from white blood cells that are known as lymphocytes. It is primarily mutation of B lymphocytes, it has a special ability to cause deficiency of immune system and also give immune escape process to avoid from self-destruction. […] The major cause of HL is change in make up of DNA of white blood cells called B lymphocytes. The proper reason of HL is not known. DNA gives cell a basic commands for its survival. Any change in DNA instruction keep the cell growing uncontrollably. Due to uncontrolled division of cell abnormal lymphocytes begin to produce and got multiply in one or more lymph nodes in particular body parts. […] 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.

• #1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7478144/

  The mechanisms that drive normal B cell differentiation and activation are frequently subverted by B cell lymphomas for their unlimited growth and survival. […] The signaling pathways that normal B cells utilize to sense antigens are frequently derailed in B cell malignancies, leading to constitutive activation of prosurvival pathways. […] These malignancies co-opt transcriptional regulatory systems that characterize their normal B cell counterparts and frequently alter epigenetic regulators of chromatin structure and gene expression. […] Recent insights into lymphoma pathogenesis are leading to the rational development of targeted therapies that may achieve cures for more of these patients. […] Many of the genetic lesions that initiate lymphomagenesis are the aberrant by-product of the enzymes that rearrange Ig segments to assemble the B cell receptor (BCR) in normal B cells.

• #1 Lymphoma – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/lymphoma/symptoms-causes/syc-20352638

  Lymphoma is an overarching term for a kind of cancer that starts in the lymphatic system. […] Lymphoma occurs when one of these types of lymphocytes grow and multiply uncontrollably. […] Like all cancers, lymphoma is the result of mutations in DNA that instruct the cells on how to grow, and the cells often grow out of control and live longer than they should. […] These particular DNA mutations affect lymphocytes, which accumulate in the lymph nodes and other parts of the lymphatic system to form tumors, crowding out healthy tissue and limiting its ability to function. […] In lymphoma, the DNA changes happen in the lymphocytes. The changes can: Lead diseased lymphocytes to grow out of control. […] Healthcare professionals aren’t sure what causes lymphoma. Lymphoma begins with changes in the DNA of a disease-fighting blood cell called a lymphocyte.

• #1 Researchers uncover mechanism that fuels growth of aggressive B-cell lymphoma – ecancer

  https://ecancer.org/en/news/24911-researchers-uncover-mechanism-that-fuels-growth-of-aggressive-b-cell-lymphoma

  Researchers uncover mechanism that fuels growth of aggressive B-cell lymphoma. Researchers from the University of Helsinki and HUS investigated the effects of recurring mutations in the KLHL6 gene in diffuse large B-cell lymphoma, the most common cancer of the lymphatic system. The KLHL6 protein is part of a cellular system tasked with disposing of excess and unnecessary proteins. In many cancers, this system is disrupted, which advances malignant growth. The researchers found that the KLHL6 protein breaks down the B-cell receptor and demonstrated that certain mutations lead to an increase in the number of these receptors. The B-cell receptor is an antibody on the surface of B-lymphocytes and a tool with which normal cells identify pathogens and fight against them. In corrupted cells, the B-cell receptor is activated in an anomalous manner, resulting in tissue growth and the development of lymphoma, says Doctoral Researcher Leo Meriranta, MD, from the University of Helsinki.

• #1 Glofitamab’s Mechanism of Action in Mantle Cell Lymphoma

  https://www.targetedonc.com/view/glofitamab-s-mechanism-of-action-in-mantle-cell-lymphoma

  Glofitamab is a bispecific antibody, meaning it has 2 binding epitopes, CD20 and CD3. This will hopefully activate T cells and cause a clonal T cell expansion or for the patients own T cells to attack the tumor. […] Glofitamab is a bispecific antibody. So, in essence it has 2 binding epitopes that will bind to CD20, which is on the malignant B-cell and also bind to CD3, which is on the patient’s T cell. And in aspects, it brings it into close proximity with the hope of activating the T cell and causing a clonal T cell expansion or to allow the patient’s own immune system their T cells in this instance, to attack and kill off the tumor cells. Again, in this way, it’s almost quasi-like an off the shelf CAR T product without the need for manufacturing. So, by using the patient’s immune system, ideally, we can avoid some of the toxicities we see with some other mechanisms or treatments that we typically use for this patient population.

• #2 Lymphomas: pathogenesis, clinical features and diagnosis – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/lymphomas-pathogenesis-clinical-features-and-diagnosis

  Lymphomas are a heterogenous group of blood cancers caused by the clonal proliferation of B or T lymphocytes. […] The cause of Hodgkin lymphoma is not known, but it does have a strong association with being infected with Epstein-Barr virus, which is implicated in 45% of cases. […] There is a strong association between immunodeficiency, such as HIV infection, and risk of developing non-Hodgkin lymphoma. […] The Epstein-Barr virus is implicated in the development of Burkitt’s lymphoma, although its overall importance as a risk factor is much less than for Hodgkin lymphoma. […] Helicobacter pylori infection is strongly associated with mucosa-associated lymphoid tissue (MALT) lymphoma, a form of non-Hodgkin lymphoma that occurs in the stomach.

• #2 Lymphoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560826/

  One of the widely accepted principles of lymphomagenesis is being on long term immunosuppressive therapies, which makes the innate immune system less able to detect and destroy cancer cells or ward off infections that could result in cancers. […] Repeated antigen stimulation in the setting of infection, autoimmune disease, or other inflammatory condition predisposes to the pathogenesis.

• #2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7478144/

  Malignant B cells often commandeer normal B cell signaling pathways to sustain their growth and survival. […] This is accomplished through either gain-of-function mutations that activate signaling effectors, loss-of-function mutations that inactivate negative regulators of signaling, or autocrine receptor activation. […] A recurring theme in lymphomas is the removal of negative regulators of NF-B. […] NF-B activation through the classical pathway is a hallmark of the ABC DLBCL subtype. […] The transcriptional repressor BCL6 is a master regulator of germinal center B differentiation and, accordingly, plays an important role in the pathogenesis of germinal center-derived lymphomas. […] BCL6 activity is dysregulated by translocation or mutation in a remarkably high proportion of DLBCL cases (50%) and in a subset of follicular lymphoma cases (10%).

• #2 Patricia Pérez – Microenvironment in lymphoma pathogenesis and therapy | IDIBAPS

  https://www.clinicbarcelona.org/en/idibaps/areas-and-programs/cancer/microenvironment-in-lymphoma-pathogenesis-and-therapy

  B-cell non-Hodgkin lymphomas (B-NHL) are haematological cancers. Their origin lies in a close cooperation between the genetic alterations of the lymphoma and the support of surrounding cells, which is known as the tumour microenvironment. […] For a treatment to be effective, it is mandatory to attack the lymphoma cells using targeted therapies, and to dismantle this protective lymphoma-microenvironment network. […] The group studies the crosstalk between lymphoma cells and its immune microenvironment. This knowledge may allow establishing the basis to manipulate these interactions and the design of novel, targeted and personalised therapies. […] The groups objective is unquestionably to conduct basic research in order to improve the treating options for lymphoma patients, characterising their mechanisms of action and resistance.

• #2 Molecular Pathogenesis of Follicular Lymphoma: From Genetics to Clinical Practice

  https://www.mdpi.com/2673-6357/3/4/41

  Importantly, FL tumor cells require interaction with the microenvironment, which sustains cell survival and proliferation. […] This review provides an updated synopsis of FL, including the molecular and cellular pathogenesis, key events of transformation, and targeted treatments. […] In the past years, molecular analyses have expanded our knowledge on the mutational landscape of FL, highlighting the importance of epigenetic modifiers, survival pathways, and the tumor microenvironment. However, elucidating the biological mechanisms that underlie the clinical heterogeneity remains a research priority. […] The genetic hallmark of FL is the t(14;18)(q32;q21) translocation, present in 80–85% of patients, which occurs in pro- or pre-B cells in the bone marrow as an error of V(D)J recombination mediated by RAG1 and 2 enzymes.

• #2 An update on Burkitt lymphoma: a review of pathogenesis and multimodality imaging assessment of disease presentation, treatment response, and recurrence | Insights into Imaging | Full Text

  https://insightsimaging.springeropen.com/articles/10.1186/s13244-019-0733-7

  Related but distinct pathologic entities are lymphomas demonstrating double or triple-hit phenomena accounting for 310% of diffuse large B cell lymphomas (DLBCL). Double hit lymphomas are characterized by the presence of both MYC and BCL-2 (or less commonly BCL-6) rearrangements, while triple-hit lymphomas demonstrate MYC, BCL-2, and BCL-6 rearrangements. These lymphoma subtypes exhibit further inhibition of apoptosis and cell survival and are associated with poorer prognosis.

• #2 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

  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. […] 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. LMP1 which is the inactive one is a protein of epstein-barr (a viral protein) and an individual from the TNFR (Tumor Necrosis Factor Receptor) super family that enacts NF-kappa B and balances developmental and apoptotic pathways. […] The tumor cells secrete cytokine and chemokine and contribute its part to get away from the immune system. For instance, the transforming growth factor (TGF-β) is secreted which represses the development of cytotoxic T-lymphocyte (CTLs), as well as the T cells, while interleukin-13 (IL-13) straightforwardly advances the development and let the HD cell lines to survive.

• #2 Researchers uncover mechanism that fuels growth of aggressive B-cell lymphoma – ecancer

  https://ecancer.org/en/news/24911-researchers-uncover-mechanism-that-fuels-growth-of-aggressive-b-cell-lymphoma

  In some of the cancer patients enrolled in the study, the KLHL6 protein was entirely absent from cells. Laboratory modelling revealed that the loss of KLHL6 in lymphoma cells increased the number of B-cell receptors manifold. The lymphoma cases where the KLHL6 protein was absent were associated with a poor prognosis. The identification of pathogenic mechanisms relevant to these patients is particularly important for improving their prognoses through drug development, Lepp says. […] The similar results obtained with different study designs are a solid indication that KLHL6 protein disruption plays a key role in some B-cell diseases, Meriranta says. He emphasises that, in the future, treatment outcomes can be improved by targeting therapies on the basis of cancer biomarkers. The new findings open avenues to tailoring therapies, as the abnormal amount and activity of the B-cell receptor can be targeted pharmacologically. However, more research is still needed, Meriranta notes.

• #3

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7478144/

  ABC DLBCL is a post-germinal center malignancy because it has mutated Ig V genes and bears a gene expression signature that includes many plasma cell-associated genes. […] Blimp-1 acts as a tumor suppressor in ABC DLBCL. […] The involvement of innate immune signaling pathways in the pathogenesis of lymphomas was uncovered by an RNA interference screen, in which knockdown of the signaling adapter MYD88 proved toxic to ABC DLBCL lines. […] MYD88 mutations in lymphomas are oncogenic and gain of function. […] Genetic and functional data suggest that chronic active BCR signaling and MYD88-dependent signaling cooperate to sustain the survival of ABC DLBCL cells.

• #3 Molecular Pathogenesis of Follicular Lymphoma: From Genetics to Clinical Practice

  https://www.mdpi.com/2673-6357/3/4/41

  The majority of these alterations are nonsense or frameshift somatic mutations leading to a loss of function and, consequently, a loss of active transcription marks (H3 lysine 4 methylation, H3K4me). […] The transcriptional regulator BCL6 is altered by somatic mutations or translocation in 5–10% of FL cases. […] Genomic alterations in genes encoding proteins in the BCR/NF-κB signaling pathway (CARD11, TNFAIP3, CD79A, CD79B, and MYD88) are present in approximately 30% of FL patients. […] The TNFRSF14 gene encodes the herpes virus entry mediator A (HVEM) which is the most recurrently altered gene via inactivating mutations, deletions, and CN-LOH. […] BCL2 mutations have been described together with the BCL2 rearrangement in around half of FL cases. […] Although TP53 mutations are identified in a low proportion of FL patients at diagnosis (6%), they are enriched in subgroups of patients with an older age, higher-risk scores, and a shorter progression-free survival.

• #3 Molecular biology of Hodgkin lymphoma | Leukemia

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

  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. […] A further group of recurrent genetic lesions mainly affects immune evasion of HRS cells. […] Overall, cHL seems unique among lymphoid malignancies in the extent and diversity of chemokine and cytokine production of the lymphoma cells, and the complexity of the microenvironmental reshaping. […] 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. […] 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.

• #3 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

  The dysfunctional of monocytes in HD patients is due to the over production of PGE2 which in turn increases IDO production by monocytes, tumor and dendritic cells. The activation of IDO restricts the accessibility of tryptophan, a basic amino acid for the synthesis of protein. These decreased levels of tryptophan make T cells to be captured in the G1 phase of the cell cycle. This shows an escape mechanism of malignant cells.

• #3 Pathogenesis and biomarkers of natural killer T cell lymphoma (NKTL) | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-019-0717-6

  In addition to the frequent STAT3 activating mutations, JAK3 activating mutations were also identified in NKTL, in 34% of cases. […] Importantly, preclinical study with Tofacitinib, a pan-JAK inhibitor, could effectively reduce tumour growth and metastatic spread of NKTL indicating that JAK3 is a promising therapeutic target for NKTL. […] A novel JAK3-specific inhibitor (PRN371) was further developed, to supersede tofacitinib in terms of specificity and durability in inhibiting JAK3 in NKTL. […] However, the single-agent regime with PRN371 did not confer complete response in mice. […] STAT3 contributes to tumour immune evasion through the accumulation and activation of tolerogenic dendritic and Treg cells, as well as the upregulation of immune checkpoint proteins such as CTLA-4, programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1).

• #4 Molecular Pathogenesis of Follicular Lymphoma: From Genetics to Clinical Practice

  https://www.mdpi.com/2673-6357/3/4/41

  FL lacking the BCL2 translocation (BCL2 − FL) comprises 10–15% of all FL patients. […] Several studies have investigated whether this subset of patients is biologically and clinically different to classical FL with BCL2 rearrangement (BCL2 + FL). […] Histological transformation of FL (tFL) into an aggressive lymphoma (mainly diffuse large B cell lymphoma) can occur during the course of the disease and affects approximately 10–20% of patients. […] The studies of paired diagnostic and tFL cases identified that tFL arises mainly through a divergent or branching evolution from a common altered precursor cell (CPC). […] The tumor-promoting activity of the TME has been explained by the development of an ecosystem that sustains the growth and survival of lymphoma cells and by the induction of mechanisms of evasion of the host antitumor immunity. […] The identification of high-risk patient groups at diagnosis in FL is still challenging. […] Several therapies targeting key alterations in the pathogenesis of FL have been approved, highlighting the importance to expand our knowledge on the mutational profile of FL.

• #4 Pathogenesis and biomarkers of natural killer T cell lymphoma (NKTL) | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-019-0717-6

  These studies suggest that inhibiting STAT3 could effectively challenge the survivability of NKTL by simultaneously disrupting its immune evasion pathway. […] The recent data on the various driving mechanisms behind NKTL attempt to unravel the complex pathogenesis driving this disease, which at present has poor treatment outcomes.

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