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)

The use of effective combination chemotherapy for all stages and subtypes of non-Hodgkin"s lymphoma (NHL) in children has resulted in a striking improvement in cure rates. Event-free survival now ranges from 70% to 90%, depending on the stage of disease and the NHL subtype. Risk-adapted therapy has resulted in a dramatic improvement in outcome for high-risk patients, at the cost of significantly increased short-term toxicity, and a reduction of therapy and toxicity for the lower-risk patient, while maintaining the excellent cure rate. Successful risk allocation of patients is dependent on the identification and continual validation of prognostic factors. The specific treatment protocol is the single most important factor predicting outcome today. Traditional prognostic factors such as stage and tumor burden are useful in selecting the intensity and length of therapy, rather than as a major indicator of likelihood of survival. In order to further improve cure rates and decrease toxicity, new biologic prognosticators need to be found and validated. Some promising avenues for study appear to be the presence or absence of adhesion molecules and of aberrant proteins that are specific to subtypes of lymphomas, such as soluble CD30 and anaplastic lymphoma kinase (ALK), the molecular classification of lymphomas on the basis of gene expression, and the evaluation of biologic markers for measuring early response to therapy.
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PMID:Pediatric non-Hodgkin's lymphoma: clinical and biologic prognostic factors and risk allocation. 1182 82

We have previously reported that plasma from patients with anaplastic lymphoma kinase (ALK)-positive lymphoma contains antibodies against the oncogenic kinase NPM-ALK protein characteristic of this disease. We investigated whether this reactivity represents a phenomenon unique to ALK-positive lymphoma by screening plasma from patients with follicular lymphoma for antibodies to BCL-2 protein. Eight out of 10 samples showed such reactivity (and in six cases gave specific staining of BCL-2-transfected cells). As these findings suggest a new biochemical approach to the identification of oncogenic proteins in lymphoma, we investigated whether antibodies present in patients with ALK-positive lymphoma can precipitate NPM-ALK in quantities which should be sufficient for further analysis. We found that plasma samples from all10 patients studied immunoprecipitated NPM-ALK asaprotein visible in silver-stained sodium dodecyl sulphatepolyacrylamide gels. Finally we demonstrated that NPM-ALK could be visualized more clearly if it were immunoprecipitated from extracts of cells in which newly synthesized proteins had been labelled with 35S and then identified by autoradiography. These results suggest a strategy for using patients' autoantibodies to screen for antibodies to other tumour-associated proteins.
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PMID:Immunochemical studies of antigenic lymphoma-associated proteins. 1184 6

The anaplastic lymphoma kinase (ALK) gene is characteristically translocated in Anaplastic Large Cell Lymphomas (ALCL) and the juxtaposition of the ALK gene to multiple partners results in its constitutive protein tyrosine kinase activity. We show here that expression of activated ALK induces the constitutive phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs. Furthermore, immunohistochemical studies demonstrate that among distinct human B and T cell lymphomas, activation of Stat3 nuclear translocation is uniquely associated with ALK expression. NPM-ALK also binds and activates Jak3; however, Jak3 is not required for Stat3 activation or for cell transformation in vitro. Moreover, src family kinases are not necessary for NPM-ALK-mediated Stat3 activation or transformation, suggesting that Stat3 may be phosphorylated directly by ALK. To evaluate relevant targets of ALK-activated Stat3, we investigated the regulation of the anti-apoptotic protein Bcl-x(L) and its role in cell survival in NPM-ALK positive cells. NPM-ALK expression caused enhanced Bcl-x(L) transcription, largely mediated by Stat3. Increased expression of Bcl-x(L) provided sufficient anti-apoptotic signals to protect cells from treatment with specific inhibitors of the Jaks/Stat pathway or the Brc-Abl kinase. These studies support a pathogenic mechanism whereby stimulation of anti-apoptotic signals through activation of Stat3 contributes to the successful outgrowth of ALK positive tumor cells.
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PMID:Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. 1185 Aug 21

CD44 is a ubiquitous multifunctional cell surface adhesion molecule family. High expression of the standard form, CD44s (CD44), and its variant form, CD44v6, has been reported to be associated with tumor dissemination in non-Hodgkin lymphoma. To evaluate the potential role of CD44 and/or CD44v6 in different entities of anaplastic large cell lymphoma (ALCL), 30 cases of systemic ALCL (sALCL; 20 cases) and primary cutaneous ALCL (cALCL; 10 cases) were compared for expression of CD44 and CD44v6 by immunohistochemical staining. Expression of CD44v6 also was analyzed with respect to expression of anaplastic lymphoma kinase (ALK) in sALCL. No difference of CD44 expression was noted between sALCL and cALCL In contrast, expression of CD44v6 was found in 18 (90%) of sALCL cases and in 5 (50%) of cALCL cases. There was no correlation between expression of CD44v6 and expression of ALK in sALCL. These results indicate that expression of CD44v6 rather than CD44 correlates with sALCL. Furthermore, these results suggest that CD44v6 and ALK may be independent predictors of risk for the systemic phenotype of ALCL.
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PMID:Association of expression of CD44v6 with systemic anaplastic large cell lymphoma: comparison with primary cutaneous anaplastic large cell lymphoma. 1186 24

Oncogenic anaplastic lymphoma kinase (ALK) fusion proteins (NPM/ALK and associated variants) are expressed in about 60% of anaplastic large cell lymphomas (ALCLs) but are absent in normal tissues. In this study, we investigated whether ALK, which is expressed at high levels in lymphoma cells, could be a target for antigen-specific cell-mediated immunotherapy. A panel of ALK-derived peptides was tested for their binding affinity to HLA-A*0201 molecules. Binding peptides were assessed for their capacity to elicit a specific immune response mediated by cytotoxic T lymphocytes (CTLs) both in vivo, in HLA-A*0201 transgenic mice, and in vitro in the peripheral blood lymphocytes (PBLs) from healthy donors. Two HLA-A*0201-restricted CTL epitopes, p280-89 (SLAMLDLLHV) and p375-86 (GVLLWEIFSL), both located in the ALK kinase domain were identified. The p280-89- and p375-86-induced peptide-specific CTL lines were able to specifically release interferon-gamma (IFN-gamma) on stimulation with ALK peptide-pulsed autologous Epstein-Barr virus-transformed B cells (LCLs) or T2 cells. Anti-ALK CTLs lysed HLA-matched ALCL and neuroblastoma cell lines endogenously expressing ALK proteins. CTL activity was inhibited by anti-HLA-A2 monoclonal antibody CR11.351, consistent with a class I-restricted mechanism of cytotoxicity. These results show the existence of functional anti-ALK CTL precursors within the peripheral T-cell repertoire of healthy donors, clearly indicating ALK as a tumor antigen and ALK-derived peptides, p280-89 and p375-86, as suitable epitopes for the development of vaccination strategies.
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PMID:ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes. 1187 85

Anaplastic large cell lymphomas (ALCL) are characterized by the expression of a chimeric protein, NPM-ALK, which originates from fusion of the nucleophosmin (NPM) and the membrane receptor anaplastic lymphoma kinase (ALK) genes. The NPM-ALK kinase, on dimerization, shows phosphotransferase activity and, through its interaction with various ALK-adapter proteins, induces cell transformation and increases cell proliferation in vitro. The chaperones heat shock proteins 90 (Hsp90) and 70 (Hsp70) play a critical role in the folding and maturation of several oncogenic protein kinases, and perturbation of Hsp90 structure affects the stability and degradation of Hsp90- and Hsp70-bound substrates. This process is triggered by benzoquinone ansamycin antibiotics, Hsp90-binding small molecules. We have studied the effect of 17-allylamino,17-demethoxygeldanamycin (17-AAG), a benzoquinone ansamycin, on NPM-ALK steady-state level in ALCL cells. Treatment with 17-AAG decreased NPM-ALK expression and phosphorylation, thus impairing its association with phospholipase C-gamma, Src homology 2 domain-containing protein (Shc), growth factor receptor-bound protein 2 (Grb2), and insulin receptor substrate-1 (IRS-1). We also observed that NPM-ALK associates with Hsp90, and incubation with 17-AAG disrupts this complex without affecting Hsp90 expression. As shown previously for other Hsp90 client proteins, destabilization of the Hsp90/NPM-ALK complex induced by 17-AAG resulted in increased binding of the chimeric protein to Hsp70, which is known to affect protein degradation. Hsp/NPM-ALK complex formation appears to be independent of NPM sequences, because we were unable to coimmunoprecipitate NPM with either Hsp90 or Hsp70. Similar to NPM-ALK, the exogenously expressed variant fusion protein TPR-ALK showed decreased expression and phosphorylation after 17-AAG treatment, suggesting that the effect of 17-AAG on ALK chimeric proteins depends on the ALK portion and not on the partner protein moiety. Our data demonstrate that NPM-ALK cell content is determined by its interaction with Hsp90 and Hsp70, and suggest that the alteration of such associations can interfere with NPM-ALK function in ALCL cells.
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PMID:Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. 1188 36

Oncogenic rearrangements of the anaplastic lymphoma kinase (ALK) gene, encoding a receptor type tyrosine kinase, are frequently associated with anaplastic large cell lymphomas. Such rearrangements juxtapose the intracellular domain of ALK to 5'-end sequences belonging to different genes and create transforming fusion proteins. To understand how the oncogenic versions of ALK contribute to lymphomagenesis, it is important to analyze the biological effects and the biochemical properties of this receptor under controlled conditions of activation. To this aim, we constructed chimeric receptor molecules in which the extracellular domain of the ALK kinase is replaced by the extracellular, ligand-binding domain of the epidermal growth factor receptor (EGFR). Upon transfection in NIH 3T3 fibroblasts, the EGFR/ALK chimera was correctly synthesized and transported to the cell surface, where it was fully functional in forming high versus low affinity EGF-binding sites and transducing an EGF-dependent signal intracellularly. Overexpression of the EGFR/ALK chimera in NIH 3T3 was sufficient to induce the malignant phenotype; the appearance of the transformed phenotype was, however, conditionally dependent on the administration of EGF. Moreover, the EGFR/ALK chimera was significantly more active in inducing transformation and DNA synthesis than the wild type EGFR when either was expressed at similar levels in NIH 3T3 cells. Comparative analysis of the biochemical pathways implicated in the transduction of mitogenic signals did not show any increased ability of the EGFR/ALK to phosphorylate PLC-gamma and MAPK compared with the EGFR. On the contrary, EGFR/ALK showed to have a consistently greater effect on phosphatidylinositol 3-kinase activity compared with the EGFR, indicating that this enzyme plays a major role in mediating the mitogenic effects of ALK in NIH 3T3 cells.
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PMID:A ligand-inducible epidermal growth factor receptor/anaplastic lymphoma kinase chimera promotes mitogenesis and transforming properties in 3T3 cells. 1191 85

Anaplastic large cell lymphomas are associated with chromosomal aberrations involving the anaplastic lymphoma kinase (ALK) gene at 2p23 that result in the expression of novel chimeric ALK proteins with transforming properties. In most of these tumors, the t(2;5)(p23;q35) generates the NPM-ALK fusion gene. However, several studies have now demonstrated that genes other than NPM may be fused to the ALK gene. We have recently described two different ALK rearrangements involving the TRK-fused gene (TFG) in which the same portion of ALK was fused to different length fragments of the 5' TFG region. These two rearrangements encoded chimeric proteins of 85 kd (TFG-ALK(S)) and 97 kd (TFG-ALK(L)), respectively. In this study, we have identified a new ALK rearrangement in which the catalytic domain of ALK was fused to a larger fragment of the TFG gene (TFG-ALK(XL)), encoding for a fusion protein of 113 kd. Genomic analysis of these three TFG-ALK rearrangements revealed that the TFG breakpoints occur at introns 3, 4, and 5, respectively, whereas the ALK breakpoints always occur in the same intron. No homologous regions or known recombination sequences were found in these regions. Transfection experiments using NIH-3T3 fibroblasts showed a similar transforming efficiency of TFG-ALK variants compared with NPM-ALK. In addition, in common with NPM-ALK, the TFG-ALK proteins formed stable complexes with the signaling proteins Grb2, Shc, and PLC-gamma. In conclusion, these findings indicate that the TFG may use a variety of intronic breakpoints in ALK rearrangements generating fusion proteins of different molecular weights, but with similar transforming potential than NPM-ALK.
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PMID:Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity. 1194 32

The sarcomatoid variant of anaplastic large cell lymphoma is one of the rarest histologic variants of this neoplasm. Due to its sarcomatoid features, it is frequently misdiagnosed as a poorly differentiated sarcoma, anaplastic carcinoma, or melanoma. We report the case of a 92-year-old woman with a sarcomatoid anaplastic large cell lymphoma mimicking a primary breast neoplasm. The patient presented with a rapidly enlarging lump in the left breast and nodules in the right axilla. The immunohistochemical profile showed reactivity for leukocyte common antigen, UCHL-1, vimentin, and CD30, but immunoexpression of anaplastic lymphoma kinase was lacking. Anaplastic large cell lymphomas are lymphoid neoplasms of T-cell/null-cell lineage that consistently express the activation marker CD30 and usually carry a gene rearrangement of the anaplastic lymphoma kinase gene. To the best of our knowledge, this is the first reported case of sarcomatoid anaplastic large cell lymphoma presenting as a primary breast neoplasm in which anaplastic lymphoma kinase expression was assessed.
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PMID:Sarcomatoid variant of anaplastic large cell lymphoma mimicking a primary breast cancer: a challenging diagnosis. 1203 65

In vitro studies suggest that resistance to chemotherapy-induced apoptosis might explain poor response to therapy in fatal cases. Actual execution of apoptosis depends on proper functioning of effector caspases, particularly caspase 3, and on the expression levels of apoptosis-regulating proteins, including Bcl-2 and the recently identified granzyme B- specific protease inhibitor 9 (PI9). Thus, high levels of caspase 3 activation should reflect proper functioning of the apoptosis pathways, resulting in chemotherapy-sensitive neoplastic cells and a favorable prognosis. We tested this hypothesis by quantifying numbers of tumor cells positive for active caspase 3, Bcl-2, and PI9, respectively, in pretreatment biopsies of systemic anaplastic large cell lymphoma (ALCL) patients and by comparing these numbers with clinical outcome. Activation of caspase 3 in more than 5% of the tumor cells was strongly correlated with a highly favorable outcome. High numbers of Bcl-2- and PI9-positive tumor cells were found to predict unfavorable prognosis. This prognostic effect was strongly related to anaplastic lymphoma kinase (ALK) status: ALK-positive ALCL had significantly higher levels of active caspase 3, while high expression of the antiapoptotic proteins Bcl-2 and PI9 was almost completely restricted to ALK-negative cases. In conclusion, high numbers of active caspase 3-positive tumor cells predict a highly favorable prognosis in systemic ALCL patients. Poor prognosis is strongly related to high numbers of Bcl-2- and PI9-positive neoplastic cells. These data support the notion that a favorable response to chemotherapy depends on an intact apoptosis cascade. Moreover, these data indicate that differences in prognosis between ALK-positive and ALK-negative ALCL might be explained by differences in expression of apoptosis-inhibiting proteins.
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PMID:Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma. 1203 86


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