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Mulder TA, Wahlin BE, Österborg A, Palma M. Targeting the Immune Microenvironment in Lymphomas of B-Cell Origin: From Biology to Clinical Application. Cancers (Basel) 2019; 11:cancers11070915. [PMID: 31261914 PMCID: PMC6678966 DOI: 10.3390/cancers11070915] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 06/21/2019] [Accepted: 06/25/2019] [Indexed: 02/08/2023] Open
Abstract
In lymphomas of B-cell origin, cancer cells orchestrate an inflammatory microenvironment of immune and stromal cells that sustain the tumor cell survival and growth, known as a tumor microenvironment (TME). The features of the TME differ between the different lymphoma types, ranging from extremely inflammatory, such as in Hodgkin lymphoma, to anergic, leading to immune deficiency and susceptibility to infections, such as in chronic lymphocytic leukemia. Understanding the characteristic features of the TME as well as the interactions between cancer and TME cells has given insight into the pathogenesis of most lymphomas and contributed to identify novel therapeutic targets. Here, we summarize the preclinical data that contributed to clarifying the role of the immune cells in the TME of different types of lymphomas of B-cell origin, and explain how the understanding of the biological background has led to new clinical applications. Moreover, we provide an overview of the clinical results of trials that assessed the safety and efficacy of drugs directly targeting TME immune cells in lymphoma patients.
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Affiliation(s)
- Tom A Mulder
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Björn E Wahlin
- Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
| | - Anders Österborg
- Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
| | - Marzia Palma
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
- Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
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Chonwerawong M, Avé P, Huerre M, Ferrero RL. Interferon-γ promotes gastric lymphoid follicle formation but not gastritis in Helicobacter-infected BALB/c mice. Gut Pathog 2016; 8:61. [PMID: 27895717 PMCID: PMC5117576 DOI: 10.1186/s13099-016-0142-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 11/14/2016] [Indexed: 12/13/2022] Open
Abstract
Background Mouse infection studies have shown that interferon-γ (IFN-γ), a T helper 1 (Th1) cytokine, is required for the development of severe pathology induced by chronic Helicobacter infection. This finding is largely based on studies performed using mice that have polarised Th1 responses i.e. C57BL/6 animals. The current work aims to investigate the role of IFN-γ in Helicobacter-induced inflammation in BALB/c mice which have Th2-polarised immune responses. Results At 7 months post-infection with Helicobacter felis, IFN-γ deficiency in BALB/c mice had no significant effect on H. felis colonisation levels in the gastric mucosa, nor on humoral responses, or gastritis severity. Ifng−/− animals with chronic H. felis infection did, however, develop significantly fewer lymphoid follicle lesions, as well as increased IL-4 splenocyte responses, when compared with infected Ifng+/+ mice (P = 0.015 and P = 0.0004, respectively). Conclusions The work shows that in mice on a BALB/c background, IFN-γ is not required for bacterial clearance, antibody responses, nor gastric inflammation. Conversely, IFN-γ appears to play a role in the development of gastric lymphoid follicles, which are precursor lesions to mucosa-associated lymphoid tissue (MALT) lymphoma. This study highlights the importance of mouse host background on the susceptibility to Helicobacter-induced pathologies.
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Affiliation(s)
- Michelle Chonwerawong
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, VIC 3123 Australia
| | - Patrick Avé
- Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris, France ; Unité de Histopathologie Humaine et Modèles Animaux, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris, France
| | - Michel Huerre
- Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris, France ; Département de Pathologie, Institut Curie, 26 Rue d'Ulm, 75248 Paris, France
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, VIC 3123 Australia ; Department of Microbiology, Monash University, Clayton, VIC Australia
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Wotherspoon AC, Du MQ, Spencer J. Gastrointestinal Lymphoma. Mucosal Immunol 2015. [DOI: 10.1016/b978-0-12-415847-4.00089-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Nakamura S, Matsumoto T. Helicobacter pylori and gastric mucosa-associated lymphoid tissue lymphoma: Recent progress in pathogenesis and management. World J Gastroenterol 2013; 19:8181-8187. [PMID: 24363507 PMCID: PMC3857439 DOI: 10.3748/wjg.v19.i45.8181] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 10/22/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
Recent progress in the research regarding the molecular pathogenesis and management of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is reviewed. In approximately 90% of cases, Helicobacter pylori (H. pylori) infection plays the causative role in the pathogenesis, and H. pylori eradication is nowadays the first-line treatment for this disease, which leads to complete disease remission in 50%-90% of cases. In H. pylori-dependent cases, microbe-generated immune responses, including interaction between B and T cells involving CD40 and CD40L co-stimulatory molecules, are considered to induce the development of MALT lymphoma. In H. pylori-independent cases, activation of the nuclear factor-κB pathway by oncogenic products of specific chromosomal translocations such as t(11;18)/API2-MALT1, or inactivation of tumor necrosis factor alpha-induced protein 3 (A20) are considered to contribute to the lymphomagenesis. Recently, a large-scale Japanese multicenter study confirmed that the long-term clinical outcome of gastric MALT lymphoma after H. pylori eradication is excellent. Treatment modalities for patients not responding to H. pylori eradication include a “watch and wait” strategy, radiotherapy, chemotherapy, rituximab immunotherapy, and a combination of these. Because of the indolent behavior of MALT lymphoma, second-line treatment should be tailored in consideration of the clinical stage and extent of the disease in each patient.
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Joosten M, Blaecher C, Flahou B, Ducatelle R, Haesebrouck F, Smet A. Diversity in bacterium-host interactions within the species Helicobacter heilmannii sensu stricto. Vet Res 2013; 44:65. [PMID: 23895283 PMCID: PMC3750284 DOI: 10.1186/1297-9716-44-65] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 07/11/2013] [Indexed: 12/18/2022] Open
Abstract
Helicobacter (H.) heilmannii sensu stricto (s.s.) is a zoonotic bacterium that naturally colonizes the stomach of dogs and cats. In humans, this microorganism has been associated with gastritis, peptic ulcer disease and mucosa associated lymphoid tissue (MALT) lymphoma. Little information is available about the pathogenesis of H. heilmannii s.s. infections in humans and it is unknown whether differences in virulence exist within this species. Therefore, a Mongolian gerbil model was used to study bacterium-host interactions of 9 H. heilmannii s.s. strains. The colonization ability of the strains, the intensity of gastritis and gene expression of various inflammatory cytokines in the stomach were determined at 9 weeks after experimental infection. The induction of an antrum-dominant chronic active gastritis with formation of lymphocytic aggregates was shown for 7 strains. High-level antral colonization was seen for 4 strains, while colonization of 4 other strains was more restricted and one strain was not detected in the stomach at 9 weeks post infection. All strains inducing a chronic active gastritis caused an up-regulation of the pro-inflammatory cytokine IL-1β in the antrum. A reduced antral expression of H+/K+ ATPase was seen in the stomach after infection with 3 highly colonizing strains and 2 highly colonizing strains caused an increased gastrin expression in the fundus. In none of the H. heilmannii s.s.-infected groups, IFN-γ expression was up-regulated. This study demonstrates diversity in bacterium-host interactions within the species H. heilmannii s.s. and that the pathogenesis of gastric infections with this microorganism is not identical to that of an H. pylori infection.
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Flahou B, Deun KV, Pasmans F, Smet A, Volf J, Rychlik I, Ducatelle R, Haesebrouck F. The local immune response of mice after Helicobacter suis infection: strain differences and distinction with Helicobacter pylori. Vet Res 2012; 43:75. [PMID: 23107128 PMCID: PMC3537685 DOI: 10.1186/1297-9716-43-75] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 10/11/2012] [Indexed: 12/11/2022] Open
Abstract
Helicobacter (H.) suis colonizes the stomach of pigs and is the most prevalent gastric non-H. pylori Helicobacter species in humans. Limited information is available on host immune responses after infection with this agent and it is unknown if variation in virulence exists between different H. suis strains. Therefore, BALB/c and C57BL/6 mice were used to compare colonization ability and gene expression of various inflammatory cytokines, as determined by real-time PCR, after experimental infection with 9 different H. suis strains. All strains were able to persist in the stomach of mice, but the number of colonizing bacteria at 59 days post inoculation was higher in stomachs of C57BL/6 mice compared to BALB/c mice. All H. suis strains caused an upregulation of interleukin (IL)-17, which was more pronounced in BALB/c mice. This upregulation was inversely correlated with the number of colonizing bacteria. Most strains also caused an upregulation of regulatory IL-10, positively correlating with colonization in BALB/c mice. Only in C57BL/6 mice, upregulation of IL-1β was observed. Increased levels of IFN-γ mRNA were never detected, whereas most H. suis strains caused an upregulation of the Th2 signature cytokine IL-4, mainly in BALB/c mice. In conclusion, the genetic background of the murine strain has a clear impact on the colonization ability of different H. suis strains and the immune response they evoke. A predominant Th17 response was observed, accompanied by a mild Th2 response, which is different from the Th17/Th1 response evoked by H. pylori infection.
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Affiliation(s)
- Bram Flahou
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke, 9820, Belgium.
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Expression of interleukin-4 and interleukin-13 and their receptors in colorectal cancer. Int J Colorectal Dis 2012; 27:1369-76. [PMID: 22441356 DOI: 10.1007/s00384-012-1456-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/07/2012] [Indexed: 02/04/2023]
Abstract
PURPOSE Interleukin-4 (IL-4) and interleukin-13 (IL-13) are anti-inflammatory and immunomodulatory cytokines which can influence cancer-directed immunosurveillance. Nothing is presently known about expression of these cytokines and their receptors (IL-4R and IL-13R) in colorectal cancer. The aim of this study was to characterize their expression in primary colorectal cancer specimens and to evaluate possible functions for this disease. METHODS Expression of IL-4, IL-13, IL-4R, and IL-13R protein was characterized by immunohistochemistry in 359 patients with Union for International Cancer Control stage I-III colorectal cancer and evaluated by uni- and multivariate analysis for their prognostic relevance. RESULTS All four proteins were expressed in colorectal cancer specimens. In the cancer cells, high IL-4, IL-13, IL-4R, and IL-13R immunoreactivity were present in 33 % (118/359), 50 % (181/359), 36 % (129/359), and 42 % (152/359), respectively. Patients with high expression of IL-4, IL-4R, and IL-13R had a lower frequency of lymph node metastases. Expression of IL-13 did not influence the frequency of lymph node metastases. However, high IL-13-immunoreactivity was associated with a better overall survival (p = 0.041). Expression of IL-4, IL-4R, or IL-13R did not influence survival. Multivariate analysis revealed that besides pT classification and tumor recurrence, IL-13 expression was an independent prognostic factor for overall survival. CONCLUSIONS Expression of IL-4, IL-4R, and IL-13R are involved in the process of local metastases in colorectal cancer, while IL-13 expression has an impact on survival. These interleukins and their receptors may become attractive targets for the treatment of colorectal cancer.
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Mimura T, Yoshida M, Nishiumi S, Tanaka H, Nobutani K, Takenaka M, Suleiman YB, Yamamoto K, Ota H, Takahashi S, Matsui H, Nakamura M, Miki I, Azuma T. IFN-γ plays an essential role in the pathogenesis of gastric lymphoid follicles formation caused by Helicobacter suis infection. ACTA ACUST UNITED AC 2011; 63:25-34. [PMID: 21631601 DOI: 10.1111/j.1574-695x.2011.00823.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In this study, we aimed to assess the role of helper T cells in the development of gastric lymphoid follicles induced by Helicobacter suis infection. C57BL/6J mice were orally inoculated with H. suis. Six weeks after infection, gastric lymphoid follicles were observed in the gastric mucosa by hematoxylin and eosin staining, and the number of follicles was increased throughout the infection period. An immunohistological examination showed that the lymphoid follicles were composed of B cells, CD4-positive helper T cells, and dendritic cells (DC). It was also revealed that the mRNA expression level of interferon-γ (IFN-γ) in the gastric mucosa was significantly increased at 12 weeks after infection. No gastric lymphoid follicles were detected in IFN-γ-deficient mice that had been infected with H. suis at 12 weeks after infection, although the development of lymphoid follicles in IL-4-deficient mice infected with H. suis was similar to that seen in the wild-type mice. In conclusion, IFN-γ, a Th1 cytokine, is deeply involved in the pathogenesis of gastric lymphoid follicles induced by H. suis infection, and it is suggested that CD4-positive T cells and DC aid in the expansion of gastric lymphoid follicles.
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Affiliation(s)
- Takuya Mimura
- Department of Internal Medicine, Division of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
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Craig VJ, Cogliatti SB, Rehrauer H, Wündisch T, Müller A. Epigenetic silencing of microRNA-203 dysregulates ABL1 expression and drives Helicobacter-associated gastric lymphomagenesis. Cancer Res 2011; 71:3616-24. [PMID: 21454413 DOI: 10.1158/0008-5472.can-10-3907] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) develops in the chronically inflamed mucosa of patients infected with the bacterial pathogen Helicobacter pylori. Here we use patient material, primary gastric lymphoma cell cultures, and a preclinical model of the disease to examine the role of microRNA (miRNA)-mediated posttranscriptional regulation--focusing in particular on miR-203 and its target ABL1--in gastric MALT lymphomagenesis. Microarray-based miRNA expression profiling revealed a strong downregulation of the putative tumor suppressor miRNA miR-203 in human MALT lymphoma samples, which resulted from extensive promoter hypermethylation of the miR-203 locus and coincided with the dysregulation of the miR-203 target ABL1 in lymphoma biopsies compared with matched adjacent normal material from the same patients. Treatment of lymphoma B cells with demethylating agents led to increased miR-203 expression and the concomitant downregulation of ABL1, confirming the epigenetic regulation of this miRNA. Ectopic reexpression of miR-203 by transfection of a human lymphoma cell line or lentiviral transduction of explanted primary MALT lymphoma cells was sufficient to prevent tumor cell proliferation in vitro. Similarly, the treatment of primary MALT lymphoma cells with the ABL inhibitors imatinib and dasatinib prevented tumor cell growth. Finally, we show that the treatment of tumor-bearing mice with imatinib induces MALT lymphoma regression in a preclinical model of the disease, implicating ABL1 in MALT lymphoma progression. In summary, our results show that the transformation from gastritis to MALT lymphoma is epigenetically regulated by miR-203 promoter methylation and identify ABL1 as a novel target for the treatment of this malignancy.
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Affiliation(s)
- Vanessa J Craig
- Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
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Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL. Blood 2011; 117:3836-46. [PMID: 21270444 DOI: 10.1182/blood-2010-07-299321] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Epidemiologic data show that the immune system may control or promote the emergence and growth of neoplastic lymphomatous clones. Conversely, systemic lymphomas, especially myeloma and chronic lymphocytic leukemia (CLL), are associated with clinical immunodeficiency. This prospective controlled study demonstrates substantially reduced circulating T helper cells, predominantly naive CD4(+) cells, in patients with nonleukemic follicular lymphoma and extranodal marginal zone lymphoma, but not in monoclonal gammopathy and early CLL. These changes were correlated with a preactivated phenotype, hyperreactivity in vitro, pre-senescence, and a T helper 2 shift of peripheral T helper cells. No prominent alterations existed in the regulatory T-cell compartment. Gene expression profiling of in vitro-stimulated CD4(+) cells revealed an independent second alteration of T helper cell physiology, which was most pronounced in early CLL but also detectable in follicular lymphoma/extranodal marginal zone lymphoma. This pattern consisted of down-regulation of T-cell receptor signaling cascades and globally reduced cytokine secretion. Both types of T-cell dysfunction may contribute to significant immunodeficiency in nonleukemic indolent B-cell lymphomas as demonstrated by unresponsiveness to hepatitis B vaccination. The precise definition of systemic T-cell dysfunction serves as the basis to study its prognostic impact, its relationship to the established influence of the lymphoma microenvironment, and its therapeutic manipulation.
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B-cell receptor signaling and CD40 ligand-independent T cell help cooperate in Helicobacter-induced MALT lymphomagenesis. Leukemia 2010; 24:1186-96. [PMID: 20428202 DOI: 10.1038/leu.2010.76] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) develops in the context of chronic inflammation caused by Helicobacter pylori infection. Most pathophysiological features of the early stages of MALT lymphomagenesis can be reproduced by experimental infection of BALB/c mice with Helicobacter species. We have previously shown that MALT lymphomas are infiltrated by T-helper cell type 2-polarized T cells and that human and murine tumor B cells carry polyreactive surface immunoglobulins. Using the murine model of the disease, in this study we show that explanted tumor B cells proliferate upon stimulation with the same panel of self and foreign antigens that are recognized by their surface antibodies. Tumor cell proliferation is strongly enhanced by the presence of intratumoral CD4(+) T cells in a CD40/CD40L-independent manner. A large proportion of tumor-infiltrating CD4(+) T cells are CD25(+)FoxP3(+) regulatory T cells (Tregs) with highly suppressive activity, which are recruited by the tumor cells through secretion of the Treg-attracting chemokines CCL17 and CCL22. The depletion of CD25(+) cells was as efficient as CD4(+) T cell depletion in blocking tumor growth in vitro and in vivo. In conclusion, our data suggest that B-cell receptor-derived signals cooperate with T-helper cell signals in driving the progression of MALT lymphoma, providing an explanation for the unique antigen dependence of this B-cell malignancy.
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Abstract
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arises against a background of chronic inflammation caused by persistent Helicobacter pylori infection. The clinical and histopathologic features of the human tumor can be reproduced by Helicobacter infection of BALB/c mice. In this study, we have analyzed the antibody sequences and antigen specificity of a panel of murine and human MALT lymphoma-derived antibodies. We find that a majority of tumors in patients as well as experimentally infected mice are monoclonal. The tumor immunoglobulin heavy chain genes have undergone somatic hypermutation, and approximately half of all tumors show evidence of intraclonal variation and positive and/or negative selective pressure. Recombinantly expressed MALT lymphoma antibodies bind with intermediate affinity to various unrelated self- and foreign antigens, including Helicobacter sonicate, immunoglobulin G (IgG), DNA, and stomach extract; antigen binding is blocked in a dose-dependent manner in competitive enzyme-linked immunosorbent assays. A strong bias toward the use of V(H) gene segments previously linked to autoantibodies and/or polyreactive antibodies in B-cell malignancies or autoimmune pathologies supports the experimental finding of polyreactivity. Our results suggest that MALT lymphoma development may be facilitated by an array of local self- and foreign antigens, providing direct antigenic stimulation of the tumor cells via their B-cell receptor.
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Ortiz-Sánchez E, Chávez-Olmos P, Piña-Sánchez P, Salcedo M, Garrido E. Expression of the costimulatory molecule CD86, but not CD80, in keratinocytes of normal cervical epithelium and human papillomavirus-16 positive low squamous intraepithelial lesions. Int J Gynecol Cancer 2007; 17:571-80. [PMID: 17386046 DOI: 10.1111/j.1525-1438.2007.00904.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Keratinocytes have been traditionally considered as nonprofessional antigen presenting cells, since multipassaged cells from skin biopsies of healthy individuals do not constitutively express major histocompatibility complex (MHC) class II or costimulatory molecules, but can be induced to do so after exposure to interferon-gamma. In normal and human papillomavirus (HPV)-infected cervical epithelium, keratinocytes are affected by a variety of soluble mediators that could modulate the expression of molecules including costimulatory proteins; however, the presence of these molecules within the cervix has been poorly studied. Therefore, our aim was to further explore the presence of costimulatory molecules on normal cervical epithelium and HPV-16 positive low squamous intraepithelial lesions (LSIL). We found in situ CD86 (but not CD80) displayed on the surface of normal keratinocytes from the spinous layer of human cervical epithelium. The presence of the protein and its messenger RNA level (evaluated by in situ hybridization) was diminished in HPV-16 positive LSILs. Although downregulation of costimulatory molecules is frequently related to cytokines expression, we did not observe differences in the presence of interleukin-10, the main cytokine that inhibits CD86 expression. Expression of CD86 on keratinocytes from normal cervical epithelium could indicate the potentiality of these cells to activate cytotoxic T cells, while the shut-off of this molecule in HPV-16 positive lesions could be a mechanism for evading host immune surveillance, resulting in the persistent HPV infection and probable progression of cervical lesions.
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Affiliation(s)
- E Ortiz-Sánchez
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del IPN, México DF
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Nakagawa M, Seto M, Hosokawa Y. Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein. Leukemia 2006; 20:929-36. [PMID: 16572204 DOI: 10.1038/sj.leu.2404192] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), involving the API2-MALT1 fusion protein, BCL10 and MALT1, have been implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma. Several lines of evidence indicated that both BCL10 and MALT1 are required for nuclear factor kappa B (NF-kappaB) activation by antigen receptor stimulation in lymphocytes, and API2-MALT1 can bypass this BCL10/MALT1 signaling pathway. Nuclear factor kappa B activation may contribute to antiapoptotic effect through NF-kappaB-mediated upregulation of apoptotic inhibitor genes. We recently demonstrated that API2-MALT1 can induce transactivation of the API2 gene through NF-kappaB activation, thus highlighting a positive feedback-loop mechanism of self-activation by upregulating its own expression in t(11;18) MALT lymphomas. We also demonstrated that API2-MALT1 possesses an antiapoptotic effect, in part, through its direct interaction with apoptotic regulators. These findings therefore led us to hypothesize that the antiapoptotic effect by API2-MALT1 may be mediated by its interaction with apoptotic regulators, on the one hand, and by NF-kappaB-mediated upregulation of apoptotic inhibitor genes on the other. We also found that BCL10 and MALT1 are shuttling between nucleus and cytoplasm, and that MALT1 can regulate the subcellular location of BCL10.
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Affiliation(s)
- M Nakagawa
- Division of Molecular Medicine, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan
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Guidoboni M, Ferreri AJM, Ponzoni M, Doglioni C, Dolcetti R. Infectious agents in mucosa-associated lymphoid tissue-type lymphomas: pathogenic role and therapeutic perspectives. ACTA ACUST UNITED AC 2006; 6:289-300. [PMID: 16507206 DOI: 10.3816/clm.2006.n.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Mucosa-associated lymphoid tissue (MALT) lymphoma probably constitutes the best in vivo model showing how complex interplay between B lymphocytes and the surrounding microenvironment may lead to a neoplastic disorder. After the seminal discovery of the pathogenic association between Helicobacter pylori and gastric MALT lymphomas, evidence suggests the possible involvement of other infectious agents in the development of MALT lymphomas arising at different body sites. Although several other bacteria (Borrelia burgdorferi, Campylobacter jejuni, and Chlamydia psittaci) and viruses (Hepatitis C virus) seem to play a role in lymphomas presenting at different locations, a possible common pathogenic mechanism is emerging. Several lines of evidence suggest that different infectious agents might provide a chronic antigenic stimulation that elicits host immune responses able to promote clonal B-cell expansion. This model is also substantiated by the increasing number of patients with MALT lymphomas who exhibit objective clinical responses after antimicrobial therapy. A multidisciplinary approach is critical to better understand the complex etiopathogenesis of MALT lymphomas with the final goal to dissect the clinicopathologic heterogeneity of these disorders and design more tailored preventive and therapeutic approaches.
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Affiliation(s)
- Massimo Guidoboni
- Immunovirology and Biotherapy Unit, Department of Pre-Clinical and Epidemiological Research, Centro di Riferimento Oncologico, IRCCS National Cancer Institute, Aviano, Italy
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Mueller A, O'rourke J, Chu P, Chu A, Dixon MF, Bouley DM, Lee A, Falkow S. The role of antigenic drive and tumor-infiltrating accessory cells in the pathogenesis of helicobacter-induced mucosa-associated lymphoid tissue lymphoma. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 167:797-812. [PMID: 16127158 PMCID: PMC1698723 DOI: 10.1016/s0002-9440(10)62052-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue type is closely linked to chronic Helicobacter pylori infection. Most clinical and histopathological features of the tumor can be reproduced by prolonged Helicobacter infection of BALB/c mice. In this study, we have addressed the role of antigenic stimulation in the pathogenesis of the lymphoma by experimental infection with Helicobacter felis, followed by antibiotic eradication therapy and subsequent re-infection. Antimicrobial therapy was successful in 75% of mice and led to complete histological but not "molecular" tumor remission. Although lympho-epithelial lesions disappeared and most gastric lymphoid aggregates resolved, transcriptional profiling revealed the long-term mucosal persistence of residual B cells. Experimental re-introduction of Helicobacter led to very rapid recurrence of the lymphomas, which differed from the original lesions by higher proliferative indices and more aggressive behavior. Immunophenotyping of tumor cells revealed massive infiltration of lesions by CD4(+) T cells, which express CD 28, CD 69, and interleukin-4 but not interferon-gamma, suggesting that tumor B-cell proliferation was driven by Th 2-polarized, immunocompetent, and activated T cells. Tumors were also densely colonized by follicular dendritic cells, whose numbers were closely associated with and predictive of treatment outcome.
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MESH Headings
- Animals
- Anti-Bacterial Agents
- Antigen-Presenting Cells/immunology
- Antigen-Presenting Cells/pathology
- Antigens/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/pathology
- Dendritic Cells/pathology
- Drug Therapy, Combination/pharmacology
- Female
- Helicobacter Infections/complications
- Helicobacter felis
- Lymphoid Tissue/pathology
- Lymphoma, B-Cell, Marginal Zone/etiology
- Lymphoma, B-Cell, Marginal Zone/immunology
- Lymphoma, B-Cell, Marginal Zone/pathology
- Lymphoma, B-Cell, Marginal Zone/physiopathology
- Mice
- Mice, Inbred BALB C
- Multigene Family
- Neoplasm Recurrence, Local
- Recurrence
- Remission Induction
- Severity of Illness Index
- Th2 Cells/pathology
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Affiliation(s)
- Anne Mueller
- Department of Microbiology and Immunology, Stanford University Medical School, Stanford, CA 94305, USA.
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17
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Trøen G, Nygaard V, Jenssen TK, Ikonomou IM, Tierens A, Matutes E, Gruszka-Westwood A, Catovsky D, Myklebost O, Lauritzsen G, Hovig E, Delabie J. Constitutive expression of the AP-1 transcription factors c-jun, junD, junB, and c-fos and the marginal zone B-cell transcription factor Notch2 in splenic marginal zone lymphoma. J Mol Diagn 2005; 6:297-307. [PMID: 15507668 PMCID: PMC1867488 DOI: 10.1016/s1525-1578(10)60525-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Splenic marginal zone lymphoma (SMZL) is a lymphoma type of putative marginal zone B-cell origin. No specific genetic alterations have yet been demonstrated in SMZL. Clinically, SMZL is a low-grade B-cell non-Hodgkin lymphoma. However, the presence of p53 mutation, 7q22-7q32 deletion or the absence of somatic hypermutations of immunoglobulin genes has been correlated with a worse prognosis. In this study, we analyzed genome-wide gene expression of 24 cases of SMZL using the microarray technique. The AP-1 transcription factors c-jun, junD, junB, and c-fos as well as Notch2 were found to be specifically up-regulated. These data were confirmed by real-time PCR and immunohistochemical staining of tissue sections. The absence of concordant high expression of the MAP kinases, the signaling cascade leading to AP-1 up-regulation, suggests autoregulation of the AP-1 transcription factors and an important role in SMZL oncogenesis. High expression of Notch2, a transcription factor that induces marginal zone B-cell differentiation, is highly suggestive for a marginal zone B-cell origin of SMZL. In addition, SMZL with the 7q deletion showed high expression of TGF-beta1 and low expression of the DNA helicase XPB, a crucial part of the nucleotide excision repair complex, possibly explaining the more aggressive clinical course of those cases.
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Affiliation(s)
- Gunhild Trøen
- Department of Pathology, The Norwegian Radium Hospital, University of Oslo, Montebello N-0310, Oslo, Norway.
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18
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Gastrointestinal Lymphoma. Mucosal Immunol 2005. [DOI: 10.1016/b978-012491543-5/50081-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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19
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Suefuji H, Ohshima K, Karube K, Kawano R, Nabeshima K, Suzumiya J, Hayabuchi N, Kikuchi M. CXCR3-positive B cells found at elevated frequency in the peripheral blood of patients with MALT lymphoma are attracted by MIG and belong to the lymphoma clone. Int J Cancer 2005; 114:896-901. [PMID: 15645433 DOI: 10.1002/ijc.20823] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Chemokine receptors mediate the migration of lymphocytes through binding of their ligands. CXCR3 is expressed in Th1 T cells; however, CXCR3 was recently reported in B-cell mucosa-associated lymphoid tissue (MALT)-type lymphoma and splenic marginal zone lymphoma. To investigate whether CXCR3-positive B lymphocytes in peripheral blood (PB) migrate to MALT and spleen, and whether the lymphoma clone is present in PB, we studied 16 cases of MALT lymphoma. In MALT cases, CXCR3-positive B lymphocytes in PB could migrate to MIG, the CXCR3 ligand. Immunohistochemical analysis showed that MALT lymphoma cells expressed CXCR3, whereas epithelial glands and/or stromal cells expressed MIG. In the PCR analysis for VH gene rearrangements, MALT lymphoma showed monoclonal or oligoclonal bands. In addition, in 8 of 16 MALT cases, the VH gene rearrangement of MALT lymphoma had the same bands as the CXCR3-positive B lymphocytes in PB. In 4 cases, the same clones of DNA sequences were confirmed in MALT lymphoma and CXCR3-positive B lymphocytes of PB. The findings support the theory that CXCR3-positive B lymphocytes in PB of MALT patients belong to the lymphoma clone and migrate to MIG-expressing mucosa-associated lymphoid tissue. It seemed to be associated with the dissemination of MALT lymphoma.
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Affiliation(s)
- Hiroaki Suefuji
- Department of Pathology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan
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20
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Ho L, Davis RE, Conne B, Chappuis R, Berczy M, Mhawech P, Staudt LM, Schwaller J. MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells. Blood 2004; 105:2891-9. [PMID: 15598810 DOI: 10.1182/blood-2004-06-2297] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overexpression. Various approaches have implicated these proteins in nuclear factor kappaB (NF-kappa B) signaling, but this has not been shown experimentally in human B cells. Immunohistochemistry showed that MALT1 is predominantly expressed in normal and malignant germinal center B cells, corresponding to the differentiation stage of MALT lymphoma. We expressed MALT1 and apoptosis inhibitor-2 API2/MALT1 in human B-cell lymphoma BJAB cells and found both transgenes in membrane lipid rafts along with endogenous MALT1 and 2 binding partners involved in NF-kappa B signaling, B-cell lymphoma 10 (BCL10) and CARMA1 (caspase recruitment domain [CARD]-containing membrane-associated guanylate kinase [MAGUK] 1). API2-MALT1 and exogenous MALT1 increased constitutive NF-kappa B activity and enhanced I kappa B kinase (IKK) activation induced by CD40 stimulation. Both transgenes protected BJAB cells from FAS (CD95)-induced death, consistent with increases in NF-kappa B cytoprotective target gene expression, and increased their proliferation rate. Expression of a dominant-negative I kappa B alpha mutant showed that these survival and proliferative advantages are dependent on elevated constitutive NF-kappa B activity. Our findings support a model in which NF-kappa B signaling, once activated in a CD40-dependent immune response, is maintained and enhanced through deregulation of MALT1 or formation of an API2-MALT1 fusion.
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Affiliation(s)
- Liza Ho
- Department of Clinical Pathology, Geneva University Hospital, Centre Medical Universitaire, Geneva, Switzerland
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21
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Yamasaki R, Yokota K, Okada H, Hayashi S, Mizuno M, Yoshino T, Hirai Y, Saitou D, Akagi T, Oguma K. Immune response in Helicobacter pylori-induced low-grade gastric-mucosa-associated lymphoid tissue (MALT) lymphoma. J Med Microbiol 2004; 53:21-29. [PMID: 14663101 DOI: 10.1099/jmm.0.05348-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
We have reported previously that heat-shock protein 60 kDa (hsp60) of Helicobacter pylori is an important antigen in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In order to investigate associations with host immune reactions and hsp60 antigen, CD40 ligand (CD40L) expression and cytokine production were analysed following stimulation with hsp60. To provide a clear antigen-driven immune response, peripheral blood mononuclear cells (PBMC) from patients with low-grade MALT lymphoma and gastritis and those from healthy volunteers were stimulated with recombinant H. pylori hsp60 and H. pylori cell lysate in the presence of cytokines (IL4 and granulocyte-macrophage colony-stimulating factor). mRNA expression was also analysed by a cDNA microarray containing 1100 genes. Expression of CD40L on PBMCs of patients with MALT lymphoma was increased by cytokines or by combination with stimulation with hsp60 antigens. The production of IL4 in PBMC cultures was increased in patients with MALT lymphoma; however, production of IFN-gamma was at low levels. DNA microarray analysis indicated increased levels of HLA-DR and integrin mRNAs. In cases of low-grade MALT lymphoma, adaptive immune responses against hsp60 may be enhanced by host factors, such as antigen presentation and T-cell activation, resulting in B-cell proliferation, which can be demonstrated during chronic H. pylori infection.
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Affiliation(s)
- Rie Yamasaki
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Kenji Yokota
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Hiroyuki Okada
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Shyunji Hayashi
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Motowo Mizuno
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Tadashi Yoshino
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Yoshikazu Hirai
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Daizou Saitou
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Tadaatsu Akagi
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Keiji Oguma
- Departments of Pathology1, Bacteriology2 and Medicine and Medical Science3, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 4Department of Infection and Immunity, Jichi Medical School, 3311-1 Yakushiji, Minami-kawauchi, Tochigi 326-0498, Japan 5National Cancer Center, Central Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
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22
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Kunisaki Y, Muta T, Yamano Y, Kobayashi Y. Detection of Two Cell Populations Corresponding to Distinct Maturation Stages in API-2/MLT-Positive Mucosa-Associated Lymphoid Tissue Lymphoma Cells Proliferating in Pleural Effusion. Int J Hematol 2003; 78:357-61. [PMID: 14686495 DOI: 10.1007/bf02983562] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A 66-year-old man was admitted to our hospital because of an intra-abdominal tumor and pleural effusion (PE). Immunoelectrophoresis of the serum showed immunoglobulin M (IgM) kappa paraprotein (7330 mg/dL). Abnormal plasmacytoid cells were seen in both the peripheral blood (PB) and the bone marrow (BM). Computed tomography scans showed extensive thickening of the gastric wall and bilateral massive PE without lymph node or pulmonary involvement. A histologic examination of the gastric mucosa showed a diffuse infiltration of small- to medium-sized lymphoid CD20-bearing cells, some of which showed a plasmacytoid morphology. Lymphoepithelial lesions were demonstrated with an immunohistochemical stain. The diagnosis was gastric mucosa-associated lymphoid tissue (MALT) lymphoma infiltrating to the PE, PB, and BM. The PE contained numerous lymphoid cells with plasmacytoid morphology that Southern blotting analysis showed to have a monoclonal IgH gene rearrangement pattern. The cells seemed to be divided into two populations according to their surface markers: mature B-cells (CD19+CD20+CD22+CD21+CD38-) and secretory B-cells (CD19+CD20(dim)CD22-CD21-CD38+). The reverse transcriptase-polymerase chain reaction technique detected the API-2/MLT transcript in the PE and PB. The patient had a good response to fludarabine treatment, which was followed with rituximab therapy. In general, gastric MALT lymphoma cells have a tendency to differentiate into plasma cells. In this article, we show that the cell character of API-2/MLT-positive MALT lymphoma is preserved even when the cells are disseminated. This is the first published case, to our knowledge, in which two differentiation stages of MALT lymphoma cells infiltrating into PE have been confirmed by flow cytometric analysis.
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MESH Headings
- Aged
- Antigens, Differentiation, B-Lymphocyte/analysis
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- B-Lymphocytes/pathology
- Cell Adhesion Molecules/analysis
- Cell Differentiation
- Cell Division
- Humans
- Immunophenotyping
- Lymphoma, B-Cell, Marginal Zone/diagnosis
- Lymphoma, B-Cell, Marginal Zone/drug therapy
- Lymphoma, B-Cell, Marginal Zone/pathology
- Male
- Neoplasm, Residual
- Oncogene Proteins, Fusion/analysis
- Pleural Effusion, Malignant/pathology
- Stomach Neoplasms/diagnosis
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/pathology
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Affiliation(s)
- Yuya Kunisaki
- Department of Internal Medicine, Kyushu Kousei-Nenkin Hospital, Fukuoka, Japan.
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23
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Seeberger H, Knörr C, Mainhardt C, Müller-Hermelink HK, Greiner A. Tumor-infiltrating T cells with similar antigen binding sites in different mucosa-associated lymphoid tissue type B cell lymphomas. Virchows Arch 2003; 442:343-8. [PMID: 12715169 DOI: 10.1007/s00428-003-0758-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2002] [Accepted: 12/06/2002] [Indexed: 10/25/2022]
Abstract
B cell lymphomas of mucosa-associated lymphoid tissue (MALT)-type arise on the background of chronic inflammation due to either autoimmunity or infection at various sites of the organism. Characteristically the tumor-infiltrating T cells found in large numbers in MALT-type lymphomas are predominantly of CD4(+) phenotype and may have impact on tumor pathogenesis. To assess whether the chromosomal translocation t(11;18)(q21; q21) that is specific for at least a subset of MALT-type lymphomas may have an impact on tumor environment, we investigated the antigen binding sites of tumor-infiltrating T cells from one t(11;18)-positive tumor of the thyroid and one t(11;18)-negative tumor of the stomach. MHC Allelotyping was performed and revealed common alleles in HLA-DR and HLA-DQ loci. Cloning and sequencing of the complementary determining region 3 in V(beta2) chains of T cell receptors demonstrated the use of identical J(beta)segments in both patients, suggestive for recognition of the same antigen. We therefore suggest that tumor-infiltrating CD4(+) T cells are tightly integrated in MALT-type lymphoma immunoarchitecture irrespective of genetic background and localization of the tumors.
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MESH Headings
- Amino Acid Sequence
- Binding Sites, Antibody/genetics
- Binding Sites, Antibody/immunology
- Chromosomes, Human, Pair 11
- Chromosomes, Human, Pair 18
- Clone Cells
- Complementarity Determining Regions/genetics
- Complementarity Determining Regions/immunology
- DNA, Neoplasm/analysis
- Flow Cytometry
- HLA-DQ Antigens/genetics
- HLA-DR Antigens/genetics
- Humans
- Immunoenzyme Techniques
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/pathology
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/immunology
- Lymphoma, B-Cell, Marginal Zone/pathology
- Molecular Sequence Data
- Polymerase Chain Reaction
- RNA, Neoplasm/analysis
- Stomach Neoplasms/genetics
- Stomach Neoplasms/immunology
- Stomach Neoplasms/pathology
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/pathology
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/immunology
- Thyroid Neoplasms/pathology
- Translocation, Genetic
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Affiliation(s)
- Harald Seeberger
- Institute of Pathology, University of Würzburg, Josef-Schneider-Strasse 2, Germany
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24
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Abstract
BACKGROUND Gastric MALT type lymphomas are distinct lymphomas that may develop after chronic antigenic stimulation caused by infection with Helicobacter pylori. An early antigen-dependent phase precedes the development of an antigen-independent phase. METHODS Narrative review. RESULTS The causative relationship between a chronic H. pylori infection and gastric MALT lymphomas has been based on epidemiological, histological, experimental and therapeutic studies. H. pylori eradication leads to a histological remission in +/- 70% of patients in early stage low-grade MALT lymphoma. There is no basis for therapeutic consequences in the case of persistent monoclonality. Full thickness invasion of the gastric wall and lymph node involvement and/or high-grade lymphoma denote the transition to an antigen-independent phase and calls for conventional treatment modalities. Molecular findings show a specific translocation in low-grade MALT lymphomas: t(11,18) and nuclear expression of bcl-10 that are highly indicative of the transition of the antigen-dependent into the antigen-independent phase. Other chromosomal and molecular findings are probably also involved. CONCLUSION The multistep pathogenesis of chronic H. pylori gastritis into low-grade gastric MALT lymphoma and tumour progression to a higher stage and grade are characterized by multiple molecular biological events. Antigen-dependency during the early phase of this malignancy is proven by the results of H. pylori eradication.
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Affiliation(s)
- H Boot
- Dept. of Gastroenterology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam.
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25
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Ghia P, Granziero L, Chilosi M, Caligaris-Cappio F. Chronic B cell malignancies and bone marrow microenvironment. Semin Cancer Biol 2002; 12:149-55. [PMID: 12027587 DOI: 10.1006/scbi.2001.0423] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Chronic B-lymphoid malignancies depend upon supportive interactions within specific microenvironments. Follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) cells accumulate in the bone marrow (BM) where they receive survival or growth signals from by-stander cells. However, they deeply differ in their interaction with the microenvironment. We propose a model where FL and CLL recreate in the BM the microenvironment most suitable to their growth by 'importing' the normal cells that usually nurse them in secondary lymphoid organs. In contrast, MM takes advantage of the actual BM microenvironment by 'instructing' it through an abnormal activation state.
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Affiliation(s)
- Paolo Ghia
- Department of Biomedical Sciences and Human Oncology, University of Torino, Italy
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26
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Timm S, Sailer M, Fuchs KH, Greiner A. First successful treatment of a primary high-grade gastric MALT lymphoma by eradication therapy for Helicobacter pylori. Gastroenterology 2001; 121:1025-6. [PMID: 11665693 DOI: 10.1053/gast.2001.28579] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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27
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Deneys V, Mazzon AM, Marques JL, Benoit H, De Bruyère M. Reference values for peripheral blood B-lymphocyte subpopulations: a basis for multiparametric immunophenotyping of abnormal lymphocytes. J Immunol Methods 2001; 253:23-36. [PMID: 11384666 DOI: 10.1016/s0022-1759(01)00338-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND OBJECTIVES Immunophenotyping has become a useful tool for the differential diagnosis of chronic B-cell lymphoproliferative disorders. The aim of this work was to determine reference values of normal B-cell subpopulations. MATERIAL AND METHODS Blood samples from 38 healthy volunteers were analyzed by multidimensional flow cytometry, using a panel of directly conjugated antibodies. Results were expressed as percent of positive B cells and as median fluorescence intensity, an indirect assessment of the expression level. RESULTS CD20, CD22, CD24, CD40, CD79a, CD79b, FMC7, CD11a, CD18, CD44 were positive in the whole B cell population, whereas CD10, CD86, CD103, CD154 and FasL were almost absent from the B-lymphocyte population. 75% were IgD positive. The kappa/lambda ratio was 1.5. CD5, CD23, CD25, CD38, CD43, CD54, CD62L, CD80 and CD95 were positive in different B-cell subpopulations. The utility of all these markers in the differential diagnosis of chronic B-cell lymphoproliferative disorders is discussed. CONCLUSION In order to interpret a pathological immunophenotype, it is necessary to refer to quantitative and qualitative values of normal B-cell subpopulations.
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MESH Headings
- Adult
- Antigens, Differentiation, B-Lymphocyte/analysis
- B-Lymphocyte Subsets/classification
- Diagnosis, Differential
- Female
- Flow Cytometry
- Fluorescence
- Humans
- Immunophenotyping/methods
- Leukemia, Lymphocytic, Chronic, B-Cell/classification
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Lymphocyte Count
- Lymphoma, B-Cell/classification
- Lymphoma, B-Cell/diagnosis
- Male
- Middle Aged
- Reference Values
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Affiliation(s)
- V Deneys
- Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Immunohaematology Laboratory, Clos Chapelle-aux-Champs, 30 BP 30.52, 1200, Brussels, Belgium.
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28
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Seeberger H, Starostik P, Schwarz S, Knörr C, Kalla J, Ott G, Müller-Hermelink HK, Greiner A. Loss of Fas (CD95/APO-1) regulatory function is an important step in early MALT-type lymphoma development. J Transl Med 2001; 81:977-86. [PMID: 11454987 DOI: 10.1038/labinvest.3780310] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Fas (CD95, APO-1) mutations were found in autoimmune diseases and some lymphomas, suggesting impairment of Fas-mediated cell death signaling that may cause tumor development. Because mucosa-associated lymphoid tissue (MALT)-type lymphoma B cells recognize autoantigens and proliferate in response to antigen and T cell-mediated signals, it is suggestive that autoreactive B cell lymphoma precursor cells may have escaped the Fas-mediated checkpoint that normally operates in healthy individuals. Using different biochemical, molecular, and functional approaches, we analyzed the Fas signaling in malignant B cells from seven MALT-type lymphomas that were additionally characterized for the t(11;18)(q21;q21) and four gastric diffuse large B cell lymphomas (DLBL). All DLBLs and three of seven MALT-type lymphomas were resistant to Fas-mediated apoptosis in vitro. Moreover, four of five MALT-type lymphomas analyzed and one of three DLBLs analyzed showed mutations in Fas mRNA transcripts but no loss of heterozygosity in the Fas promotor region. Alternative mechanisms of resistance to apoptosis, such as decreased expression of Fas or production of soluble Fas were not operative. Therefore, it is suggestive that a subgroup of MALT-type lymphoma B cells, irrespective of t(11;18)(q21;q21), escape the censoring Fas pathway by mutating and inactivating Fas. This identifies a key regulatory step in early MALT-type lymphomagenesis.
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Affiliation(s)
- H Seeberger
- Institute of PathologyUniversity of Würzburg, Würzburg, Germany
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29
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Barth TF, Bentz M, Döhner H, Möller P. Molecular aspects of B-cell lymphomas of the gastrointestinal tract. CLINICAL LYMPHOMA 2001; 2:57-64. [PMID: 11707871 DOI: 10.3816/clm.2001.n.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The B-cell lymphomas of the gastrointestinal (GI) tract have represented a field of extensive research ever since a close association was shown with such chronic inflammatory processes as Helicobacter pylori infection. Evidence suggested that the mucosa-associated lymphoid tissue induced by inflammation and autoimmune processes is the environment that gives rise to the small-cell lymphomas of the GI tract (eg, extranodal marginal zone B-cell lymphoma according to Revised European-American Classification of Lymphoid Neoplasms and the World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissue). The small B-cell lymphoma may then progress to highly malignant variants. The B-cell lymphomas of the GI tract may present a stepwise model for lymphomagenesis and progression. This review covers molecular biology and molecular cytogenetic aspects that lead to new insights into the biology of GI lymphomas and potential prognostic factors.
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MESH Headings
- Cell Transformation, Neoplastic
- Disease Progression
- Gastrointestinal Neoplasms/genetics
- Gastrointestinal Neoplasms/immunology
- Gastrointestinal Neoplasms/pathology
- Helicobacter Infections/complications
- Humans
- Lymphoma, B-Cell/genetics
- Lymphoma, B-Cell/immunology
- Lymphoma, B-Cell/pathology
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/immunology
- Lymphoma, B-Cell, Marginal Zone/pathology
- Prognosis
- Translocation, Genetic
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Affiliation(s)
- T F Barth
- Institute of Pathology, University of Ulm, Ulm, Germany.
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Hjelmström P. Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines. J Leukoc Biol 2001; 69:331-339. [PMID: 11261778 DOI: 10.1189/jlb.69.3.331] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
Chronic inflammation is a complex pathophysiological process with accumulation of mononuclear cells seen in response to invading pathogens, neoplastic transformation, or autoimmune recognition of self-antigens. The inflammatory process has evolved to facilitate effective elimination of pathogens and tumors and it is normally transient and turned off when the causative stimulus has been eliminated. Occasionally, however, the process is sustained for a long time and can lead to severe tissue damage. This is seen in organ-specific autoimmune diseases such as rheumatoid arthritis, Sjögren's syndrome, and Hashimoto's thyroiditis, but also in infectious diseases such as Helicobacter pylori-induced gastritis. Disturbingly, many of these chronic inflammatory diseases are associated with an increased risk for neoplastic transformation and development of lymphomas. This review summarizes experimental evidence suggesting that chronic inflammation involves ectopic de novo formation of organized lymphoid tissue and that this lymphoid neogenesis is regulated by expression of homing chemokines.
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Affiliation(s)
- P Hjelmström
- Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
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Kalla J, Stilgenbauer S, Schaffner C, Wolf S, Ott G, Greiner A, Rosenwald A, Döhner H, Müller-Hermelink HK, Lichter P. Heterogeneity of the API2-MALT1 gene rearrangement in MALT-type lymphoma. Leukemia 2000; 14:1967-74. [PMID: 11069033 DOI: 10.1038/sj.leu.2401918] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The translocation t(11;18)(q21;q21), which is the most frequent chromosomal aberration in extranodal marginal zone B cell lymphomas of MALT-type, was characterised in a series of 34 biopsies, including 18 gastric non-Hodgkin's lymphomas (NHL) of MALT-type, six MALT-type NHL of extragastral origin and 10 extranodal large B cell lymphomas (LBL). Based on fluorescence in situ hybridisation, STS-PCR analysis and screening of genomic PAC libraries, a physical map of contiguous DNA probes on chromosome 11 was constructed containing the anti-apoptotic genes API2 and API1 adjacent to the translocation breakpoint. RACE-PCR experiments revealed MALT1 the chromosome 18-derived fusion partner of API2, which has also been reported recently by other groups. RT-PCR analysis and DNA sequencing demonstrated the expression of an API2-MALT1 fusion transcript in 18/24 gastral and extragastral MALT-type lymphomas. In none of 10 LBLs was a translocation specific RT-PCR product detected. Five variants of the fusion transcript were identified and in all instances the open reading frame of the fused portion of the MALT1 gene was maintained. The molecular analysis of these variants allowed the design of optimised assays for the diagnosis of the API2-MALT1 gene rearrangement.
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MESH Headings
- Caspases
- Chromosome Mapping
- Chromosomes, Human, Pair 11/genetics
- Chromosomes, Human, Pair 11/ultrastructure
- Chromosomes, Human, Pair 18/genetics
- Chromosomes, Human, Pair 18/ultrastructure
- Humans
- In Situ Hybridization, Fluorescence
- Inhibitor of Apoptosis Proteins
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/pathology
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/pathology
- Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
- Neoplasm Proteins/genetics
- Oncogene Proteins, Fusion/genetics
- Polymerase Chain Reaction
- Proteins/genetics
- Salivary Gland Neoplasms/genetics
- Salivary Gland Neoplasms/pathology
- Stomach Neoplasms/genetics
- Stomach Neoplasms/pathology
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/pathology
- Translocation, Genetic
- Ubiquitin-Protein Ligases
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Affiliation(s)
- J Kalla
- Organisation komplexer Genomé, Deutsches Krebsforschungszentrum, Heidelberg, Germany
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Thorbecke GJ, Ponzio NM. Reverse immune surveillance: an adaptive mechanism used by tumor cells to facilitate their survival and growth. Semin Cancer Biol 2000; 10:327-30. [PMID: 11100879 DOI: 10.1006/scbi.2000.0350] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Abstract
The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL.In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly.In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues.In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel “proto-oncogenes” involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcγRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described.
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Abstract
AbstractThe rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL.In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly.In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues.In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel “proto-oncogenes” involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcγRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described.
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