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)

Peripheral NK/T-cell neoplasms are an uncommon group of diseases that show distinct racial and geographic variation. The prognostic significance of the T-cell phenotype has been clearly defined in recent studies by using modern lymphoma classification systems. However, within this heterogenous group of neoplasms, some have a more favorable prognosis, such as ALK-positive anaplastic large-cell leukemia (ALCL) and primary cutaneous ALCL, and some have ultimately fatal courses with standard chemotherapy programs (e.g., hepatosplenic gammadelta T-cell lymphomas). Further, unlike the benefits observed with CHOP chemotherapy in the treatment of diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphomas (PTCL), other than ALK-positive ALCL, are relatively chemoresistant to this regimen. Given disease rarity and biological heterogeneity, advances in diagnosis, prognosis and treatment have lagged behind DLBCL. Recently, however, studies are emerging that focus specifically on PTCLs with the ultimate goal of better understanding disease biology and developing more effective therapies.
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PMID:Prognosis and primary therapy in peripheral T-cell lymphomas. 1907 97

T-cell neoplasms encompass a heterogeneous group of relatively rare disease entities. This review, focused on lymphoblastic tumors (T-ALL/LBL) and nodal-based peripheral T-cell lymphomas (PTCL), summarizes recent advances in the molecular characterization of these diseases. In T-ALL/LBL, molecular subgroups delineated by gene expression profiling correlate with leukemic arrest at specific stages of normal thymocyte development and different oncogenic pathways, and seem to be of interest for prognosis prediction. Angioimmunoblastic T-cell lymphoma (AITL), one of the most common PTCL entities, comprises neoplastic cells with a molecular signature similar to normal follicular helper T cells, and this cellular derivation might account for several of the peculiar aspects of this disease. Except in ALK-positive anaplastic large cell lymphoma, defined by ALK gene fusions, chromosomal translocations are otherwise rare in PTCLs, but some recurrent rearrangements might be associated with distinct lymphoma subtypes. In PTCL, not otherwise specified (PTCL, NOS), novel molecular biomarkers of potential therapeutic interest have been recently identified.
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PMID:Molecular classification of T-cell lymphomas. 1923 83

Deregulation of the sonic hedgehog (SHH) signaling pathway has been implicated in several cancers but has not been explored in T-cell lymphomas. Here, we report that the SHH/GLI1 signaling pathway is activated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL). We show that SHH, but not its transcriptional effector GLI1, is amplified in ALK+ ALCL tumors and cell lines, and that SHH and GLI1 proteins are highly expressed in ALK+ ALCL tumors and cell lines. We also show that inhibition of SHH/GLI1 signaling with cyclopamine-KAAD, as well as silencing GLI1 gene expression by small interfering (si)RNA, decreased cell viability and clonogenicity of ALK+ ALCL cells. Transfection of wild-type or mutant NPM-ALK into 293T cells showed that only wild-type NPM-ALK increased GLI1 protein levels and activated SHH/GLI1 signaling as shown by increase of CCND2 mRNA levels. Inhibition of ALK tyrosine kinase and phosphatidylinositol 3-kinase (PI3K)/AKT or forced expression of pAKT down-regulated or up-regulated SHH/GLI1 signaling, respectively. Inhibition of GSK3beta in 293T cells also increased protein levels of GLI1. In conclusion, the SHH/GLI1 signaling pathway is activated in ALK+ ALCL. SHH/GLI1 activation is the result of SHH gene amplification and is further mediated by NPM-ALK through activation of PI3K/AKT and stabilization of GLI1 protein. There is a positive synergistic effect between the SHH/GLI1 and PI3K/AKT pathways that contributes to the lymphomagenic effect of NPM-ALK.
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PMID:Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma. 1924 33

There have been no prior large population-based studies focusing on cutaneous lymphomas (CL) in the United States. Using the Surveillance, Epidemiology and End Results (SEER) program data, we analyzed age-adjusted CL incidence rates (IRs) and survival rates by sex and race/ethnicity. There were 3884 CLs diagnosed during 2001-2005. Cutaneous T-cell lymphomas (CTCLs) accounted for 71% (age-adjusted incidence rate [IR] = 7.7/1 000 000 person-years), whereas cutaneous B-cell lymphomas(CBCLs) accounted for 29% (IR = 3.1/1 000 000 person-years). Males had a statistically significant higher IR of CL than females (14.0 vs 8.2/1 000 000 person-years, respectively; male-female IR ratio [M/F IRR] = 1.72; P < .001). CL IRs were highest among blacks and non-Hispanic whites (both 11.5/1 000 000 person-years), followed by Hispanic whites (7.9) and Asian/Pacific Islanders (7.1). The CTCL IR was highest among blacks (10.0/1 000 000 person-years), whereas the CBCL IR was highest among non-Hispanic whites (3.5). Over the past 25 years, the CL IR increased from 5.0/1 000 000 person-years during 1980-1982 to 14.3 during 2001-2003. During 2004-2005, the CL IR was 12.7. This recent apparent change could be incomplete case ascertainment or potential leveling off of IRs. CLs rates vary markedly by race and sex, supporting the notion that they represent distinct disease entities.
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PMID:Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases. 1927 31

ITK-SYK, a novel fusion tyrosine kinase (FTK) resulting from a recurrent t(5;9)(q33;q22), was recently identified in a poorly understood subset of peripheral T-cell lymphomas. However, the biochemical and functional properties of ITK-SYK are unknown. Here we demonstrate that ITK-SYK is a catalytically active tyrosine kinase that is sensitive to an established inhibitor of SYK. The expression of ITK-SYK, but not SYK, transformed NIH3T3 cells, inducing loss of contact inhibition and formation of anchorage-independent colonies in soft agar, in a kinase activity-dependent manner. ITK-SYK is unusual among FTKs in having an N-terminal phosphatidylinositol 3,4,5-trisphosphate-binding pleckstrin homology (PH) domain. Introduction of a well characterized loss-of-function mutation (R29C) into the PH domain of ITK-SYK inhibited its phosphorylation, markedly reduced its catalytic activity, and abrogated its ability to activate the ERK signaling pathway and to transform NIH3T3 cells. Although ITK-SYK was membrane-associated, ITK-SYK-R29C was not. However, each of these properties could be recovered by retargeting ITK-SYK-R29C back to the plasma membrane by the addition of an N-terminal myristylation sequence. Consistent with a model in which ITK-SYK requires PH domain-mediated binding to phosphatidylinositol 3,4,5-trisphosphate generated by phosphatidylinositol 3-kinase (PI3K), ITK-SYK activity was reduced by pharmacological inhibition of PI3K and increased by co-expression with a constitutively active form of PI3K. Together, these findings identify ITK-SYK as an active, transforming FTK dependent upon PH domain-mediated membrane localization, identify a novel mechanism for activation of an oncogenic FTK, and suggest ITK-SYK as a rational therapeutic target for t(5;9)(q33;q22)-positive lymphomas.
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PMID:The lymphoma-associated fusion tyrosine kinase ITK-SYK requires pleckstrin homology domain-mediated membrane localization for activation and cellular transformation. 1953 34

Anaplastic large cell lymphoma (ALCL) is a main type of T-cell lymphomas and comprises three distinct entities: systemic anaplastic lymphoma kinase (ALK) positive, systemic ALK(-) and cutaneous ALK(-) ALCL (cALCL). Little is known about their pathogenesis and their cellular origin, and morphological and immunophenotypical overlap exists between ALK(-) ALCL and classical Hodgkin lymphoma (cHL). We conducted gene expression profiling of microdissected lymphoma cells of five ALK(+) and four ALK(-) systemic ALCL, seven cALCL and sixteen cHL, and of eight subsets of normal T and NK cells. The analysis supports a derivation of ALCL from activated T cells, but the lymphoma cells acquired a gene expression pattern hampering an assignment to a CD4(+), CD8(+) or CD30(+) T-cell origin. Indeed, ALCL display a down-modulation of many T-cell characteristic molecules. All ALCL types show significant expression of NFkappaB target genes and upregulation of genes involved in oncogenesis (e.g. EZH2). Surprisingly, few genes are differentially expressed between systemic and cALCL despite their different clinical behaviour, and between ALK(-) ALCL and cHL despite their different cellular origin. ALK(+) ALCL are characterized by expression of genes regulated by pathways constitutively activated by ALK. This study provides multiple novel insights into the molecular biology and pathogenesis of ALCL.
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PMID:Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma. 1965 61

The aim of the study was to investigate the expression of angio- and lymphangiogenic molecules (vascular endothelial growth factors VEGF and VEGF-C and their receptors Flt-1, KDR, and Flt-4) in non-Hodgkin lymphomas (NHL) treated in the pre-rituximab era. Pre-therapeutic lymph-node biopsies from 155 patients with NHL (64 follicular lymphomas (FLs), 47 de novo diffuse large B-cell lymphomas (DLBCL) and 44 peripheral T-cell lymphomas (PTCL)) were stained by in situ hybridization and immunohistochemistry. Tumor cell expression of VEGF, VEGF-C and their receptors was detected in most of the analyzed biopsies. In FL, diffuse intratumoral VEGF staining correlated with shorter overall survival (OS) (p = 0.008) and diffuse KDR staining was associated with a higher risk of histologic transformation (p = 0.05). In DLBCL, high KDR expression predicted poor treatment response (p = 0.03) and had a significant adverse impact on OS (p < 0.001). In PTCL, diffuse tissue distribution of VEGF mRNA correlated with an unfavorable 5-year OS (p = 0.004).
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PMID:Expression level, tissue distribution pattern, and prognostic impact of vascular endothelial growth factors VEGF and VEGF-C and their receptors Flt-1, KDR, and Flt-4 in different subtypes of non-Hodgkin lymphomas. 1970 53

Here we report that T-cell lymphomas characterized by the expression of anaplastic lymphoma kinase (ALK+ TCL) fail to express the TNFalpha and frequently display DNA methylation of the TNFalpha gene promoter. While only a subset of the ALK+ TCL-derived cell lines showed a high degree of the promoter methylation, all 6 showed low to nondetectable expression of the TNFalpha mRNA, and none expressed the TNFalpha protein. All 14 ALK+ TCL tissue samples examined displayed some degree of the TNFalpha promoter methylation, which was the most prominent in the distal portion of the the promoter. Treatment with a DNA methyltransferase inhibitor, 5'-aza-2'-deoxy-cytidine (5-ADC), reversed the promoter methylation and led to the expression of TNFalpha mRNA and protein. Furthermore, in vitro DNA methylation of the promoter impaired its transcriptional activity in the luciferase reporter assay. This impairment was seen even if only either distal or proximal portion were methylated, with methylation of the former exerting a more profound inhibitory effect. Notably, the ALK+ TCL cell lines uniformly expressed the type 1 TNFalpha receptor (TNF-R1) protein known to transduce the TNFalpha-induced pro-apoptotic signals. Moreover, exogenous TNFalpha inhibited growth of the ALK+ TCL cell lines in a dose-dependent manner and induced activation of the members of the cell apoptotic pathway: Caspase 8 and caspase 3. These findings provide additional rationale for the therapeutic inhibition of DNA methyltransferases in ALK+ TCL. They also suggest that treatment with TNFalpha may be highly effective in this type of lymphoma.
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PMID:Lack of TNFalpha expression protects anaplastic lymphoma kinase-positive T-cell lymphoma (ALK+ TCL) cells from apoptosis. 1971 36

Peripheral T-cell lymphomas constitute a heterogeneous group with regard to diagnosis, treatment and prognosis. Efforts have been made to combine novel techniques with cytology and immunochemistry in order to more precisely define these entities. Molecular profiling has contributed to novel insights in the biology of T-cell lymphoma. Regarding anaplastic large cell lymphoma, low expression T-cell receptor signalling and high STAT3 target signatures have been associated with the ALK-positive subgroup. Gene expression profiling differentiates angioblastic T-cell lymphoma from other T-cell malignancies, suggests that the normal counterpart of lymphoma cells are follicular helper T cells, and supports the involvement of vascular endothelial growth factor deregulation in its physiopathology. In peripheral T-cell lymphoma unspecified, gene profiling suggests the normal counterpart of tumour cells are activated CD4(+) or CD8(+) T-lymphocytes, delineates prognostic groups depending on the proliferative signature, and suggests therapeutic options aimed at regulating nuclear factor-kappaB and platelet-derived growth factor receptor-alpha phosphorylation. Gene expression profiling of primary cutaneous T cell lymphomas highlighted the importance of abnormal methylation patterns, suggested a pivotal role for JUNB/AP-1, and defined a predictive model for response to interferon-alpha. In conclusion, gene expression profiling is beginning to change the pathological classification, the prognosis profiles and the therapeutic approach in T-cell lymphomas.
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PMID:Peripheral T-cell lymphoma gene expression profiling and potential therapeutic exploitations. 1991 18

Cell lineage is the major criterion by which lymphomas are classified. Immunohistochemistry has greatly facilitated lymphoma diagnosis by detecting expression of lineage-associated antigens. However, loss or aberrant expression of these antigens may present diagnostic challenges. Anaplastic large cell lymphoma is a T-cell lymphoma that shows morphologic and phenotypic overlap with classical Hodgkin's lymphoma, which is a tumor of B-cell derivation. Staining for the B-cell transcription factor, paired box 5 (PAX5), has been suggested to be helpful in this differential, as it is positive in most classical Hodgkin's lymphomas, but absent in anaplastic large cell lymphomas. In this study we report four systemic T-cell anaplastic large cell lymphomas that were positive for PAX5 by immunohistochemistry, with weak staining intensity similar to that observed in classical Hodgkin's lymphoma. All diagnoses were confirmed by a combination of morphologic, phenotypic, and molecular criteria. Three cases were anaplastic lymphoma kinase (ALK) negative and one was ALK positive. PAX5 immunohistochemistry was negative in 198 additional peripheral T-cell lymphomas, including 66 anaplastic large cell lymphomas. Unexpectedly, although PAX5 translocations were absent, all evaluable PAX5-positive anaplastic large cell lymphomas showed extra copies of the PAX5 gene locus by fluorescence in situ hybridization (FISH). In contrast, only 4% of PAX5-negative peripheral T-cell lymphomas had extra copies of PAX5. We conclude that aberrant expression of PAX5 occurs rarely in T-cell anaplastic large cell lymphomas, and may be associated with extra copies of the PAX5 gene. PAX5-positive lymphomas with morphologic features overlapping different lymphoma types should be evaluated with an extensive immunohistochemical panel and/or molecular studies to avoid diagnostic errors that could lead to inappropriate treatment. As PAX5 overexpression causes T-cell neoplasms in experimental models, PAX5 may have contributed to lymphomagenesis in our cases.
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PMID:PAX5-positive T-cell anaplastic large cell lymphomas associated with extra copies of the PAX5 gene locus. 2011 7


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