Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of latent membrane protein 2 (LMP2A) during B-cell development leads to global alterations in gene transcription similar to those seen in Hodgkin Reed-Sternberg cells of Hodgkin lymphoma (HL). Along with the consistent detection of LMP2A in Epstein-Barr virus-associated HL, this implicates a role for LMP2A in the pathogenesis of HL. We have shown that LMP2A constitutively activates the Notch1 pathway to autoregulate the LMP2A promoter. To determine whether constitutive activation of the Notch pathway is important for LMP2A-mediated alterations in B-cell development in vivo, TgE-LMP2A-transgenic mice were intercrossed with mice expressing loxP-flanked Notch1 genes and Cre recombinase. B cells from TgE Notch1(lox/lox)-CD19(+/Cre) mice have an increase in immunoglobulin M and CD43 and a decrease in CD5 expression in the bone marrow compared with TgE Notch1(lox/lox) mice, indicating the LMP2A signal for developmental aberrations is impaired in the absence of Notch1. Real-time reverse-transcribed polymerase chain reaction analysis reveals that LMP2A requires the Notch1 pathway to alter levels of B cell-specific transcription factors, E2A and EBF. Interestingly, Notch1 appears to be important for LMP2A-mediated survival in low interleukin-7. We propose that LMP2A and the Notch1 pathway may cooperate to induce the alterations in B-cell identity seen in Hodgkin Reed-Sternberg cells.
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PMID:Epstein-Barr virus latent membrane protein 2A exploits Notch1 to alter B-cell identity in vivo. 1881 81

The Hodgkin cell line U-HO1 was established from a malignant pleural effusion of a 23-yr-old male patient during the end stage of refractory nodular sclerosing classical Hodgkin lymphoma (cHL). Since its establishment in 2005, U-HO1 has maintained stable characteristics in vitro and has a doubling time of about 4 days under standard culture conditions. U-HO1 forms typical Reed/Sternberg cells in suspension, is EBV negative, lacks HLA-ABC- but expresses HLA-D- proteins/CD74 and surface exposes CD15 together with CD30 in the absence of CD19 and CD20. Karyotype analysis of U-HO1 revealed a hyperdiploid karyotype with multiple clonal aberrations. Most significant is an elongated chromosome 2, der(2)t(2;10)(q35;q16.1)add(2)(p13). CGH analysis revealed the following imbalances: ish cgh dim(1)(p13p31)(p12q21), enh(2)(p13p23), dim(4)(q31.3qter), enh(6)(q22q27), enh(12), enh(18),enh(20)(q13.1pter). FISH analysis showed about six-fold amplification of REL and BCL-11A, thus, U-HO1 is prototypical for cHL in every aspect tested so far. Compared to other HL cell lines, U-HO1 proved far less genetically aberrant suggesting that U-HO1's imbalances suffice to cause the full-blown phenotype of primary refractory cHL.
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PMID:[U-HO1. A new cell line derived from a primary refractory classical Hodgkin lymphoma]. 1882 Sep 24

CD19 is a pan B-cell surface receptor expressed from pro-B-cell development until its down-regulation during terminal differentiation into plasma cells. CD19 represents an attractive immunotherapy target for cancers of lymphoid origin due to its high expression levels on the vast majority of non-Hodgkin's lymphomas and some leukemias. A humanized anti-CD19 antibody with an engineered Fc domain (XmAb5574) was generated to increase binding to Fcgamma receptors on immune cells and thus increase Fc-mediated effector functions. In vitro, XmAb5574 enhanced antibody-dependent cell-mediated cytotoxicity 100-fold to 1,000-fold relative to an anti-CD19 IgG1 analogue against a broad range of B-lymphoma and leukemia cell lines. Furthermore, XmAb5574 conferred antibody-dependent cell-mediated cytotoxicity against patient-derived acute lymphoblastic leukemia and mantle cell lymphoma cells, whereas the IgG1 analogue was inactive. XmAb5574 also increased antibody-dependent cellular phagocytosis and apoptosis. In vivo, XmAb5574 significantly inhibited lymphoma growth in prophylactic and established mouse xenograft models, and showed more potent antitumor activity than its IgG1 analogue. Comparisons with a variant incapable of Fcgamma receptor binding showed that engagement of these receptors is critical for optimal antitumor efficacy. These results suggest that XmAb5574 exhibits potent tumor cytotoxicity via direct and indirect effector functions and thus warrants clinical evaluation as an immunotherapeutic for CD19(+) hematologic malignancies.
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PMID:Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. 1882 63

The specificity and sensitivity of CD19, CD20, CD79a, and PAX5 for detection of B-cell lineage lymphoma/leukemia derivation was determined on tissue microarrays containing 148 Hodgkin lymphomas, 358 B-cell and 16 T-cell lymphomas, 50 myelomas, and 69 acute leukemias. In mature lymphoid neoplasms, receiver-operating characteristic curve analysis showed CD20 to be the most sensitive, and CD20 and CD79a the most specific markers for B-lineage derivation. CD19 had the weakest specificity, because it was expressed in 3 T-cell lymphomas, but its sensitivity was better than CD79a. In Hodgkin lymphoma cases, the presence of B-cell markers in Hodgkin and Reed-Sternberg cells decreased in the following order: PAX5>CD20>CD79a>CD19. CD19 and PAX5 were not detectable in myelomas. In acute leukemia, CD20 turned to be the most specific, and PAX5 and CD19 the most sensitive markers for B-lineage derivation. In conclusion, an optimal B-cell lineage panel for daily routine on paraffin-embedded tissues should consist of CD20 and CD79a, and eventually, PAX5 for mature lymphoid neoplasms and PAX5 and CD19, and eventually, CD20 in (acute) precursor cell leukemias, because they cover most of the sensitivity and specificity needed.
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PMID:Diagnostic utility of the B-cell lineage markers CD20, CD79a, PAX5, and CD19 in paraffin-embedded tissues from lymphoid neoplasms. 1883 17

Despite major advances in the treatment of non-Hodgkin lymphoma (NHL), including the use of chemotherapeutic agents and the anti-CD20 antibody rituximab, the majority of patients eventually relapse, and salvage treatments with non-cross-resistant compounds are needed to further improve patient survival. Here, we evaluated the antitumor effects of the microtubule destabilizing agent monomethyl auristatin E (MMAE) conjugated to the humanized anti-CD19 antibody hBU12 via a protease-sensitive valine-citrulline (vc) dipeptide linker. hBU12-vcMMAE induced potent tumor cell killing against rituximab-sensitive and -resistant NHL cell lines. CD19 can form heterodimers with CD21, and high levels of CD21 were reported to interfere negatively with the activity of CD19-targeted therapeutics. However, we observed comparable internalization, intracellular trafficking, and drug release in CD21(low) and CD21(high), rituximab-sensitive and -refractory lymphomas treated with hBU12-vcMMAE. Furthermore, high rates of durable regressions in mice implanted with these tumors were observed, suggesting that both rituximab resistance and CD21 expression levels do not impact on the activity of hBU12-vcMMAE. Combined, our data suggest that hBU12-vcMMAE may represent a promising addition to the treatment options for rituximab refractory NHL and other hematologic malignancies, including acute lymphoblastic leukemia.
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PMID:Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas. 1914 85

B-cell malignancies seem to be particularly amenable to immunotherapy and as such make particularly attractive targets for adoptive T-cell therapy. Murine T cells gene-modified to express a chimeric immune receptor specific for CD19+ (aCD19z) efficiently kill CD19 B-cell lymphoma cells in vitro. aCD19z T cells also secrete high levels of interleukin-2 during culture with target cells in a CD86 independent manner. aCD19z T cells proved effective at eradicating established B-cell lymphoma in a syngeneic model system when combined with a lymphodepleting preconditioning regimen. In mice deficient of T, B, and natural killer cells (severe combined immunodeficient/Beige), aCD19z T cells efficiently eradicated long-term (13 d) established tumors with 100% of treated animals remaining tumor free for greater than 77 days. Although gene-modified CD4+ and CD8+ were both active in this setting, poor engraftment by CD8+ T cells coupled with the rigorous expansion of CD4+ cells in the Balb/c background suggests that CD4+ T cells may be playing a predominant role in lymphoma rejection in this model. Taken together, the therapeutic effectiveness of aCD19z T cells in this model supports a recently opened phase 1 trial of this receptor in non-Hodgkin lymphoma.
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PMID:Eradication of established B-cell lymphoma by CD19-specific murine T cells is dependent on host lymphopenic environment and can be mediated by CD4+ and CD8+ T cells. 1924 79

Flow cytometry (FC) immunophenotyping of fine-needle aspiration (FNA) has been reported to be useful in the diagnosis of non-Hodgkin lymphomas (NHL). The authors reviewed their 5-year experience to assess the ability that FC has in improving the diagnostic capacity of cytomorphology in the diagnosis and subclassification of NHL according to the World Health Organization's classification. FC was performed on 252 FNA specimens. These included 123 cases of NHL (89 primary and 34 recurrent lymphomas). The FC immunophenotyping included CD3, CD4, CD8, CD10, CD19, CD20, CD45, and kappa/lambda antibodies combinations in the screening panel and additional panels for B or T lineage in the presence of positivity for lymphoma after the screening. An immunologic diagnosis was obtained by FC in 90% (111/123) of cases identified as NHL. FC was able to improve the total number of NHL detected in 8 cases where cytomorphology had failed to do so. In 7% (9/123) of cases, FC failed to formulate a diagnostic hypothesis owing to the sample inadequacy; 2 cases (2%) were not identified as lymphomas by FC (1 of them considered only "suggestive" also by cytomorphology); 1 case was not identified neither by FC, nor by cytomorphology. In cases having a histologic follow-up, levels of diagnostic sensitivity and specificity of the combination cytomorphology/FC were 97% and 94%, respectively. FC applied to FNA enhanced the diagnostic potential of cytologic diagnosis and subclassification of NHL, thus avoiding the need for invasive surgical biopsies in many cases.
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PMID:Utility of flow cytometry immunophenotyping in fine-needle aspirate cytologic diagnosis of non-Hodgkin lymphoma: A series of 252 cases and review of the literature. 1924 81

Primary presentation of intradural non-Hodgkin lymphoma is rare. Recently, B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) have been recognized as an important pathologic subtype. When MALT lymphomas present in the central nervous system (CNS), they are distinguishable from primary high-grade CNS lymphomas. We present the clinicopathologic features of 5 patients with primary CNS MALT lymphoma treated at our institution from 1999 to 2006. Four out of 5 patients were women, and all patients presented with headaches, focal motor deficits, or cranial nerve palsy. Radiologic studies demonstrated ill-defined dural masses in 3 and well-defined masses in 2 patients. Pathology revealed small to medium-sized cells with a moderate amount of cytoplasm and irregular nuclear borders, expressing pan B-cell markers (CD19, CD20, and CD79a) but lacking CD10, CD23, and cyclin D1, confirming low-grade MALT lymphoma. Plasma cells were encountered in all the biopsies with variable reactive T-cell infiltration. wedge chain restriction was seen in 3 patients. Therapy consisted of either surgical resection, whole-brain radiation, or systemic or intrathecal chemotherapy. There was no evidence of recurrence or systemic relapse in 4 patients at 4 years of follow-up. One patient died in 2 months, unrelated to CNS lymphoma. This case series illustrates the rare occurrence of low-grade dural B-cell lymphoma and the need to consider this entity in the differential diagnosis of CNS lesions.
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PMID:Primary central nervous system mucosa-associated lymphoid tissue lymphoma: case report and literature review. 1952 85

A 40-year-old female, HIV positive, stage C, since 4 years, complained of a right cervical lymph node swelling. Two years before, the patient had been diagnosed with follicular B-cell non-Hodgkin lymphoma (FL); she had been treated with four cycles of multiagent chemotherapy plus rituximab, the last cycle being administered 10 months before coming to our attention. An ultrasound (US) guided fine-needle cytology (FNC) showed an atypical lymphoid cell proliferation. The phenotype evidenced by flow cytometry (FC) analysis was D5: 10%, CD19: 49%, CD23: 10%, FMC7: 0%, CD10: 40%, CD10/19: 40%, lambda light chain 40%, kappa light chain 0%. FDG-positron emission tomography (PET/CT) scan showed positivity in the corresponding cervical area. Since low LDH values and a reduced lymph node size were observed, the lymph node was therefore excised; the histology revealed a reactive hyperplastic lymph node with florid follicular pattern. A subsequent PCR analysis, performed on DNA extracted from a whole histological section, did not evidence IgH rearrangement. The patient is currently undergoing strict clinical and instrumental follow-up, including PET every 3 months; after 13 months, she is alive without recurrence of lymphoma. Clonal B-cell populations in non-lymphomatous processes have been described in mucosa-associated lymphoid cell populations and reactive lymph nodes, and are considered non-malignant, antigen driven, proliferations of B-lymphocytes determined by an abnormal response to bacterial or viral antigen stimulation. The present case occurred in an HIV patient and was clinically complex because of the patient's history of FL. This experience suggests much attention in the evaluation of radiological, cytological, and FC data and in clinical correlation in patients suffering from autoimmune or immunodeficiency syndromes.
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PMID:Clonal B-cell population in a reactive lymph node in acquired immunodeficiency syndrome. 1958 4

We evaluated the diagnostic utility of flow cytometry immunophenotyping in bone marrow aspirates and peripheral blood, in the assessment of mature B-cell non-Hodgkin lymphoma (MBNHL). We analyzed 356 cases of MBNHL received for immunophenotyping over a 4 year period. All cases were reviewed, correlated with biopsy specimen (lymph node and splenectomy). Discrepant cases were re-evaluated. Common subtypes included chronic lymphocytic leukemia (CLL) (243 cases, 68.5%), follicular lymphoma (30 cases, 8.5%), mantle cell lymphoma (20 cases, 5.5%), splenic marginal zone lymphoma (18 cases, 5%), hairy cell leukemia (18 cases, 5%). CD5+/CD23+ had a high positive predictive value (PPV) for diagnosing CLL whereas CD5+/CD23- had a high negative predictive value (NPV) for diagnosing mantle-cell lymphoma (MCL). Limited panel of 9 antibodies mainly CD19, CD5, CD23, CD10, FMC7, kappa, lambda, CD3 and CD20 help diagnose more than 92% of cases of MBNHL. Minimal diagnostic panels become important in countries with limited resources.
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PMID:Immunophenotyping of mature B-cell non Hodgkin lymphoma involving bone marrow and peripheral blood: critical analysis and insights gained at a tertiary care cancer hospital. 1981 31


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