Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is controversy in the literature as to whether anaplastic large-cell lymphoma of B-cell phenotype is related to the t(2;5)-positive T- or 'null' cell lymphoma of the same morphology. We report a study of 24 lymphomas with morphological features of anaplastic large-cell lymphoma which expressed one or more B-cell markers and lacked T-lineage markers. Clinical features were more in keeping with large B-cell lymphoma than with classical t(2;5)-positive anaplastic large-cell lymphoma, and immunostaining for anaplastic lymphoma kinase (ALK) protein provided no evidence for the (2;5) translocation (or one of its variants). The staining patterns for CD20 and CD79 were typical of diffuse large B-cell lymphoma, CD30 expression was variable, and most cases (15/22) lacked epithelial membrane antigen (EMA). These findings support the view that 'B-cell anaplastic large-cell lymphoma' is unrelated to t(2;5)-positive (ALK-positive) lymphoma, and that it represents a morphological pattern occasionally encountered among diffuse large B-cell lymphomas. By the same reasoning, most tumours diagnosed as 'ALK-negative anaplastic large-cell lymphoma of T-cell or null phenotype' probably belong to the spectrum of peripheral T-cell lymphomas.
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PMID:Anaplastic large-cell lymphomas of B-cell phenotype are anaplastic lymphoma kinase (ALK) negative and belong to the spectrum of diffuse large B-cell lymphomas. 1088 8

This study reports the first use of gene array technology for the identification of a tumor-specific marker in lymphoid neoplasms. The differential gene expression of 31 hematopoietic cell lines, representing most major lymphoma subgroups of B- and T-cell origin, was assessed by hybridizing labeled complementary DNA to Atlas human expression arrays containing 588 genes. Genes known to be specific for B, T, or myelomonocytic lineages were appropriately identified in the arrays, validating the general utility of this approach. One gene, clusterin, not previously known to be expressed in lymphoid neoplasms, was specifically found in all 4 anaplastic large-cell lymphoma (ALCL) cell lines, but not in any of the 27 remaining tumor lines. Using a monoclonal antibody against clusterin, its differential expression was confirmed by Western blotting and immunohistochemistry. A total of 198 primary lymphomas (representing most major lymphoma subtypes), including 36 cases of systemic ALCL, were surveyed for clusterin expression by immunohistochemistry and Western blotting. All of the 36 ALCL cases marked for clusterin, with most cases showing moderate to strong staining in the majority of neoplastic cells. Clusterin expression was not related to expression of anaplastic lymphoma kinase-1. With 2 exceptions, none of the remaining 162 non-ALCL cases marked with the clusterin antibody, including Hodgkin disease and primary cutaneous ALCL. In reactive lymphoid tissues, only follicular dendritic cells and fibroblastic reticular cells exhibited staining. Clusterin is a highly conserved glycoprotein implicated in intercellular and cell matrix interactions, regulation of the complement system, lipid transport, stress responses, and apoptosis. Although its function in ALCL is unknown, the unique expression of clusterin within this category of lymphoma provides an additional marker for the diagnosis of ALCL. This study illustrates the enormous potential of gene array technologies for diagnostic marker discovery. (Blood. 2000;96:398-404)
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PMID:Detection of differentially expressed genes in lymphomas using cDNA arrays: identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas. 1088 98

Chemokine receptors mediate the migration of lymphocytes through the binding of soluble ligands, and their expression is differentially regulated in lymphocyte subsets. The pattern of chemokine receptor expression in T-cell non-Hodgkin lymphoma has not been previously studied. Using a panel of mouse monoclonal antibodies, we studied the immunohistochemical expression of the Th1-associated chemokine receptor CXCR3 in 141 patients with T-cell lymphoma, and we studied the receptors CCR4 and CCR5 and some of their ligands in a subset of these tumors. Expression of CXCR3 was typical of the smaller T cells in angioimmunoblastic lymphoma (15 of 18 patients), angiocentric lymphoma (3 of 3 patients), histiocyte-rich tumors (4 of 5 patients), and unspecified T-cell lymphomas (17 of 39 patients). CXCR3 expression was seen in only 1 of 15 patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma. In contrast, all ALK-positive tumors showed diffuse reactivity for the Th2-associated receptor CCR4 (5 of 5 patients). CCR4 expression was also a consistent feature of the large-cell transformation of mycosis fungoides. CCR5 expression showed no consistent association with any T-cell tumor type. The chemokines Mig (CXCR3 ligand), TARC (CCR4 ligand), and MCP-2 (CCR5 ligand) were detected in intratumoral blood vessels and histiocytes. Mig was also coexpressed by a subset of CXCR3-positive tumor cells in 6 of 20 lymphomas. MCP-2 was highly expressed in stromal cells in 3 patients with nodal involvement by cutaneous T-cell lymphoma. As with normal T-cell subsets, we demonstrated that there is frequent differential expression of chemokine receptors in T-cell tumors, which may explain, in part, the distinctive patterns of spread in different tumor subtypes. (Blood. 2000;96:685-690)
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PMID:Expression pattern of T-cell-associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma. 1088 35

Oncogenic anaplastic lymphoma kinase (ALK) fusion proteins (nucleophosmin-ALK [NPM-ALK] and other variants) are expressed in many cases of anaplastic large-cell lymphoma (ALCL) but are absent from normal tissues. The possibility that ALK proteins are immunogenic was investigated with the use of an immunocytochemical technique to screen plasma from ALK-positive ALCL on transfectants expressing ALK proteins and by an in vitro kinase assay. Circulating antibodies against NPM-ALK protein were present in all ALK-positive ALCL patients (11 out of 11 cases) studied while 10 patients also had antibodies recognizing normal ALK protein. Weak antibodies reactive with NPM-ALK (which may represent anti-NPM autoantibodies) were detected by the in vitro kinase assay in 3 of the 10 control samples (but not by immunocytochemistry). The presence of anti-ALK antibodies may be relevant to the relatively good prognosis of ALK-positive ALCL. The immunocytochemical technique for detecting anti-ALK activity is simple and semiquantative and may provide a means of detecting B-cell responses to other tumor-associated molecules. (Blood. 2000;96:1605-1607)
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PMID:Immune response to the ALK oncogenic tyrosine kinase in patients with anaplastic large-cell lymphoma. 1094 17

Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all non-Hodgkin lymphomas according to the recent Non-Hodgkin Lymphoma Classification Project. As defined in the revised European-American classification of lymphoid neoplasms (REAL), ALCL is a neoplasm of T-cell or null-cell lineage; 20% to 60% of cases are associated with the t(2;5)(p23;q35) translocation. ALCL commonly involves nodal as well as a wide variety of extranodal sites, although primary or secondary involvement of bone is rare. We describe the case of a 71-year-old man with stage IE T-cell ALCL, monomorphic variant, arising in the left anterior fifth rib and involving adjacent soft tissue without other sites of disease. The monomorphic histologic features hindered the initial recognition of this neoplasm as ALCL. However, strong uniform CD30 antigen expression and subsequent demonstration of the t(2;5)(p23;q35) translocation and anaplastic lymphoma kinase (ALK) immunoreactivity led to the correct diagnosis. We identified only 5 reported cases of T-cell and null-cell ALCL arising in bone and only 2 of these cases involved a single bone site. All 5 previously reported cases were ALCL of the classic type. We report a case of ALCL that is unique to our knowledge. This case of monomorphic ALCL was localized to bone and tumor cells contained the t(2;5)(p23;q35) translocation.
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PMID:Anaplastic large cell lymphoma arising in bone: report of a case of the monomorphic variant with the t(2;5)(p23;q35) translocation. 1097 33

Neutrophil-rich anaplastic large cell lymphoma (ALCL) is an uncommon morphologic variant of ALCL. We report 2 cases of neutrophil-rich T-cell ALCL that presented as scalp masses in HIV-positive men. Histologically, the neoplastic cells extensively infiltrated the dermis and subcutaneous tissue. The neoplastic cells strongly expressed CD30 and were of T-cell lineage, positive for CD3 and CD45RO, and negative for CD20. The neoplastic cells were negative for anaplastic lymphoma kinase-1. Numerous admixed neutrophils also were present, representing up to 70% of all cells in some microscopic fields. Neither patient had peripheral blood leukocytosis. One patient had relative neutrophilia, 79% (0.79; reference range, 50%-70% [0.50-0.70]). The absolute CD4 counts were 160 cells/microL (160 x 10(6)/L) and 150 cells/microL (150 x 10(6)/L), respectively (reference range, 431-1,623/microL [431-1,623 x 10(6)/L]). Both patients were treated with multiagent chemotherapy but died of Pneumocystis carinii pneumonia within 6 months of diagnosis. In our review of the literature, we identified 5 similar T-cell cases, including 1 in an HIV-positive patient. Neutrophil-rich T-cell ALCL is a rare morphologic variant of ALCL that should be considered in the histologic evaluation of neutrophil-rich biopsy specimens.
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PMID:Neutrophil-rich anaplastic large cell lymphoma of T-cell lineage. A report of two cases arising in HIV-positive patients. 1160 Nov 44

Despite its clinical and histological heterogeneity, anaplastic large cell lymphoma (ALCL) is now a well-recognized clinicopathological entity accounting for 2% of all adult non-Hodgkin's lymphomas (NHL) and about 13% of pediatric NHL. Immunophenotypically, ALCL are of T cell (predominantly) or Null cell type; by definition, cases expressing B cell antigens are officially not included in this entity. The translocation (2;5)(p23;q35) is a recurring abnormality in ALCL; 46% of the ALCL patients bear this signature translocation. This translocation creates a fusion gene composed of nucleophosmin (NPM) and a novel receptor tyrosine kinase gene, named anaplastic lymphoma kinase (ALK). The NPM-ALK chimeric gene encodes a constitutively activated tyrosine kinase that has been shown to be a potent oncogene. The exact pathogenetic mechanisms leading to lymphomagenesis remain elusive; however, the synopsis of evidence obtained to date provides an outline of likely scenarios. Several t(2;5) variants have been described; in some instances, the breakpoints have been cloned and the genes forming a new fusion gene with ALK have been identified: ATIC-ALK, TFG-ALK and TPM3-ALK. Cloning the translocation breakpoint and identifying the ALK and NPM genes provided tools for screening material from patients with ALCL using various approaches at the chromosome, DNA, RNA, or protein level: positive signals in the reverse transcriptase-polymerase chain reaction (RT-PCR) and the immunostaining with anti-ALK monoclonal antibodies (McAb) serve as the most convenient tests for detection of the t(2;5) NPM-ALK since the fusion gene and ALK protein expression do not occur in normal or reactive lymphoid tissue. The wide range of NPM-ALK positivity reported in different series appears to be dependent on the inclusion and selection criteria of the ALCL cases studied. Overall, however, 43% of ALCL cases were NPM-ALK+ (83% of pediatric ALCL vs 31% of adult ALCL). Occasional non-ALCL B cell lymphomas (4%) with diffuse large cell and immunoblastic histology and Hodgkin's disease cases (3%) were NPM-ALK-, but these data are questionable. The aggregate results indicate that, in contrast to primary nodal (systemic) ALCL, the t(2;5) may be present in only 10-20% of primary cutaneous ALCL and rarely, if at all, in lymphomatoid papulosis, a potential precursor lesion; however, these 10-20% positive cases were not confirmed by anti-ALK McAb immunostaining and may represent an overestimate. Positivity for NPM-ALK is associated to various degrees with the following parameters: 44% and 45% of ALCL cases with T cell and Null cell immunophenotype, respectively, are positive, whereas only 8% of cases with a B cell immunoprofile are positive; the mean age of positive patients is significantly younger than that of negative patients; positive cases carry a better overall prognosis (but not in all studies). Recently, the homogenous category of ALK lymphoma ('ALKoma') has emerged as a distinct pathological entity within the heterogenous group of ALCL. The fact that patients with ALK lymphomas experience significantly better overall survival than ALK- ALCL demonstrates further that analysis of ALK expression has important prognostic implications. The term ALK lymphoma signifies a switch in the use of the diagnostic criteria: cases are selected on the basis of a genetic abnormality (the ALK rearrangement), instead of the review of morphological or immunophenotypical features which are clearly more prone to disagreement and controversy. Since its initial description in 1985 ALCL has become one of the best characterized lymphoma entities.
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PMID:Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. 1099 99

We report on the analysis of a murine anaplastic lymphoid cell line TS1G6, established recently by interleukin (IL)-9 transfection. TS1G6 revealed a highly characteristic pattern of large anaplastic cells with mononuclear, binuclear, or multinuclear cells resembling Hodgkin (H) or Sternberg-Reed (SR) cells. This cell line is tumorigenous after injection of as few as 10(4) lymphoma cells into nude or immunocompetent C57Bl/6 mice and leads to death from progressive disease of all treated animals within a few weeks. The histological analysis of these tumors revealed a diffuse large cell malignant lymphoma that is morphologically almost identical to human anaplastic large cell lymphoma (ALCL). The lymphoma cells did not show overexpression of the anaplastic lymphoma kinase (ALK) gene, which is found in about 50% of the cases of human ALCL. Thus, this model may be an animal model for an important subset of human ALCL. The cytokine profile, which is of the T helper 2 type, showed strong parallels to the human lymphoma counterpart. Mice suffering from such lymphomas could not be cured with a regimen using high dose cyclophosphamide similar to many ALCL patients. Such an animal model for ALCL has not yet been recognized, but may provide the basis for investigating new antitumor immunotherapies in a fully immunocompetent host.
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PMID:An animal model for anaplastic large cell lymphoma in the immunocompetent syngeneic C57Bl/6 mouse. 1104 69

Anaplastic large cell lymphoma (ALCL) is a distinct entity of non-Hodgkin lymphoma, characterized by a proliferation of pleomorphic large lymphoid cells that express CD30. Recent studies have found that a subset of ALCL aberrantly expresses a chimeric anaplastic lymphoma kinase (ALK) protein as a result of t(2;5)(p23;q35) or variant translocations. ALK-positive ALCLs feature good prognosis, but some of them lead to poor outcomes. Since CD56 is expressed in some ALCLs, its clinical significance was examined in a series of T/null cell type ALCLs. Of 143 patients, 83 (58%) showed ALK-positive staining, and of 140 patients, 25 (18%) expressed CD56. The ALK-positive subgroup was characterized by a younger age of onset (P <.0001), lower serum lactate dehydrogenase level (P =.01), better performance status (P =.03), less frequent extranodal involvement (P =.01), lower international prognostic index (IPI) categories (P =.002), and superior survival (P =.0009) in comparison with the ALK-negative group, suggesting that ALK is a specific marker defining a distinct subtype. CD56(+) cases showed a significantly poor prognosis overall (P =.002) as well as in both ALK-positive and ALK-negative subgroups (P =.02 and P =.04, respectively). Multivariate analysis confirmed that CD56 is independent of other prognostic factors, including IPI. Although CD56(+) cases showed a higher incidence of bone involvement, no other differences in clinicopathologic parameters were found between the CD56(+) and CD56(-) groups. These findings suggest that CD56 is not a marker to identify a distinct subtype of ALCL, but a strong clinical prognostic factor. Effective therapeutic approaches should be explored for high-risk ALCL patients, who can be identified by means of a prognostic model, including CD56.
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PMID:Prognostic significance of CD56 expression for ALK-positive and ALK-negative anaplastic large-cell lymphoma of T/null cell phenotype. 1104 76

The subgroup of T/null-cell primary systemic anaplastic large cell lymphoma that expresses anaplastic lymphoma kinase (ALK) constitutes a distinctive clinicopathologic entity that exhibits a broad morphologic spectrum. The examples predominated by small cells or showing a mixed cell population can be difficult to recognize as being neoplastic. We report four such cases with a remarkably hypocellular granulation tissue-like appearance, mimicking an inflammatory or reparative process. All patients were young and presented with lymphadenopathy in multiple sites. The lymph node biopsies showed a hypocellular appearance, with wide separation of the small to medium-sized lymphoid cells by edematous or fibromyxoid stroma. There were interspersed spindly neoplastic cells resembling myofibroblasts, sometimes forming short, sweeping fascicles, as well as histiocytes. Occasional large cells with atypical nuclei were identified. The larger lymphoid cells tended to form cuffs around the venules. In two cases, the capsule and fibrous trabeculae were markedly broadened with increased spindly cells, mimicking inflammatory pseudotumor of lymph node. Immunostaining showed dispersed and clustered CD30+ ALK+ cells, confirming a diagnosis of anaplastic large cell lymphoma. In conclusion, a diagnosis of hypocellular anaplastic large cell lymphoma requires a high index of suspicion. The young age of the patients and the presence of perivascular cuffs of larger lymphoid cells should provide the strongest clues to the correct diagnosis.
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PMID:Hypocellular anaplastic large cell lymphoma mimicking inflammatory lesions of lymph nodes. 1107 56


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