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)

CD4+CD56+ hematodermic neoplasm (CD4+CD56+HN) is an aggressive hematopoietic malignancy with distinct clinicopathologic and immunophenotypic features that commonly involve the skin, bone marrow, and blood. Differentiation from cutaneous myelomonocytic leukemia (c-AML) may be exceedingly difficult and requires extensive phenotyping. The molecular mechanisms involved in the development of CD4+CD56+HN are largely unresolved. Moreover, recurrent chromosomal alterations have not yet been precisely defined in CD4+CD56+HN and c-AML. In the present study an integrated genomic analysis using expression profiling and array-based comparative genomic hybridization (CGH) was performed on lesional skin biopsy samples of patients with CD4+CD56+HN and c-AML. Our results demonstrate that CD4+CD56+HN and c-AML show distinct gene-expression profiles and distinct patterns of chromosomal aberrations. CD4+CD56+HN is characterized by recurrent deletion of regions on chromosome 4 (4q34), chromosome 9 (9p13-p11 and 9q12-q34), and chromosome 13 (13q12-q31) that contain several tumor suppressor genes with diminished expression (Rb1, LATS2). Elevated expression of the oncogenes HES6, RUNX2, and FLT3 was found but was not associated with genomic amplification. We noted high expression of various plasmacytoid dendritic-cell (pDC)-related genes, pointing to the cell of origin of this malignancy.
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PMID:Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. 1706 54

Human 8p11 stem cell leukemia/lymphoma syndrome usually presents as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase that plays a pathogenic role in hematopoietic transformation. We found that ZNF198-FGFR1 activated both the AKT and mitogen activated protein kinase (MAPK) prosurvival signaling pathways, resulting in elevated phosphorylation of the AKT target FOXO3a at T32 and BAD at S112, respectively. These phosphorylated residues subsequently sequestered the proapoptotic FOXO3a and BAD to 14-3-3 to prevent apoptosis. We used a peptide-based 14-3-3 competitive antagonist, R18, to disrupt 14-3-3-ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by ZNF198-FGFR1 compared with control cells. Moreover, purified recombinant transactivator of transcription (TAT)-conjugated R18 proteins effectively transduced into human leukemia cells and induced significant apoptosis in KG-1a cells expressing FGFR1OP2-FGFR1 fusion tyrosine kinase but not in control HL-60 and Jurkat T cells. Surprisingly, R18 was only able to dissociate FOXO3a, but not BAD as previously proposed, from 14-3-3 binding and induced apoptosis partially through liberation and reactivation of FOXO3a. Our findings suggest that 14-3-3 integrates prosurvival signals in FGFR1 fusion-transformed hematopoietic cells. Disrupting 14-3-3-ligand association may represent an effective therapeutic strategy to treat 8p11 stem cell MPD.
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PMID:14-3-3 Integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1-transformed hematopoietic cells. 1738 61

SS18-SSX fusion genes resulting from a chromosomal translocation t(X;18)(p11.2;q11.2) are a genetic hallmark of synovial sarcoma. Although such cytogenetic or molecular aberrations have mostly been detected by fluorescence in situ hybridization or reverse transcription-polymerase chain reaction, the expression of SS18-SSX has been poorly investigated at a cellular or tissue level. In this study, biotinylated tyramide (BT)-based in situ hybridization (ISH) was performed to detect SS18-SSX transcripts using formalin-fixed, paraffin-embedded tissues from 15 synovial sarcomas. Digoxigenin-labeled cRNA probes flanking the fusion points of SS18-SSX1 and SS18-SSX2 were generated by in vitro transcription, and hybridized signals were detected by a streptavidin-biotin complex method after chemical enhancement with BT. The localizations of signals were compared with the immunohistochemical expressions of epithelial or neuroectodermal markers and those of cell adhesion including cytokeratins (CAM5.2, AE1/AE3, CK7), epithelial membrane antigen, E-cadherin, beta-catenin, c-erbB-2 (HER2/neu), CD56, and claudin-1. The ISH signals of the SS18-SSX transcripts were identified in 13 synovial sarcomas, and their fusion types correlated with those determined by reverse transcription-polymerase chain reaction. In biphasic tumors, the ISH signals tended to localize to epithelial areas, whereas spindle-cell areas or monophasic fibrous tumors showed a less intense or focal expression pattern. Notably, the expression patterns of AE1/AE3, CK7, and c-erbB-2 often colocalized with the ISH signals (7 of 11 cases positive for each marker). Our results suggest that BT-based ISH can be used as a molecular technique for the detection of SS18-SSX using formalin-fixed, paraffin-embedded tissues.
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PMID:Molecular detection of SS18-SSX fusion gene transcripts by cRNA in situ hybridization in synovial sarcoma using formalin-fixed, paraffin-embedded tumor tissue specimens. 1747 Nov 53

Many factors such as genetic, developmental and hormonal are involved in mammalian sex determination. The relative importance and the mutual interactions among those factors are obscure. Study of cytogenetic mosaicism involving sex chromosomes may help to further unravel the mysterious process. We report a fetus with a mosaic karyotype, 45,X/46,X,idic(Y)(qter-p11.3::p11.3-qter), with unambiguous male external genitalia and a defect in the interventricular septum of the heart. Genotype of this fetus was extensively studied by technologies including sequencing of SRY (sex-determining region on the Y chromosome) gene, G-banding, FISH (fluorescence in situ hybridization) and SKY (spectral karyotyping). A markedly higher percentage of Y-containing cells was observed in the gonads (55%) than in the amniotic fluid (17%) and placental villi (11%), which was considered to be the major reason why the fetus did not have ambiguous genitalia.
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PMID:Delineation of an isodicentric Y chromosome in a mosaic 45,X/46,X,idic(Y)(qter-p11.3::p11.3-qter) fetus by SRY sequencing, G-banding, FISH, SKY and study of distribution in different tissues. 1756 77

Inflammatory myofibroblastic tumors (IMTs) are rare soft tissue tumors occurring primarily in children and young adults. ALK gene rearrangements have been identified in this neoplasm, with fusion of the ALK gene at 2p23 to a number of different partner genes. Metaphase cytogenetic analyses of these tumors have been relatively few, however, and may help to identify additional variant partners. We report on an IMT from a 2-year-old boy with a karyotype of 45,XY,der(2)inv(2)(p23q12)del(2)(p11.1p11.2),-22. FISH showed ALK-RANBP2 fusion in this tumor. The breakpoint was cloned and the fusion was confirmed, making this the third reported case of IMT with ALK-RANBP2 fusion. In addition, we identified the ALK fusion partner in a previously reported IMT with t(2;17)(p23;q23) as CLTC, a gene reported to be involved in four other IMTs, and showed that the breakpoint involved a novel ALK-CLTC fusion. FISH evaluation of nine other IMTs identified CLTC as the fusion partner in one additional case, but RANBP2 was not involved in the remaining eight IMTs, suggesting that the variant partners involved in ALK rearrangements in IMTs are diverse.
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PMID:RANBP2 and CLTC are involved in ALK rearrangements in inflammatory myofibroblastic tumors. 1765 52

The 8p12 myeloproliferative syndrome is a rare, generally aggressive chronic myeloproliferative disorder (MPD). The hallmark of this MPD is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. In MPD cells FGFR1 is fused to several partners. The most frequent partner genes are BCR, CEP110, FOP, and ZNF198, localized on 22q11, 9q33, 6q27, and 13q12, respectively. We report here the tenth case of translocation (8;9)(p12;q33) in an acute myelomonocytic leukemia and provide a review of the literature that points to common syndrome features: the t(8;9)(p11;q33) MPD transforms rapidly, and always in myelomonocytic leukemia, with a possible B- or T-lymphoid involvement, which may include tonsil invasion. The FGFR1-MPD seems refractory to current chemotherapies and is not sensitive to imatinib. Currently, only the patients with bone marrow transplantation stand a chance of survival.
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PMID:Common features of myeloproliferative disorders with t(8;9)(p12;q33) and CEP110-FGFR1 fusion: report of a new case and review of the literature. 1809 25

We have investigated two patients with acquired chromosomal rearrangements, a male presenting with a t(1;9)(p34;q34) and B cell progenitor acute lymphoid leukemia and a female presenting with a t(8;12)(p11;q15) and the 8p11 myeloproliferative syndrome. We determined that the t(1;9) fused ABL to SFPQ (also known as PSF), a gene mapping to 1p34 that encodes a polypyrimidine tract-binding protein-associated splicing factor. The t(8;12) fused CPSF6, a cleavage and polyadenylation specificity factor, to FGFR1. The fusions were confirmed by amplification of the genomic breakpoints and RT-PCR. The predicted oncogenic products of these fusions, SFPQ-ABL and CPSF6-FGFR1, are in-frame and encode the N-terminal domain of the partner protein and the entire tyrosine kinase domain and C-terminal sequences of ABL and FGFR1. SFPQ interacts with two FGFR1 fusion partners, ZNF198 and CPSF6, that are functionally related to the recurrent PDGFRalpha partner FIP1L1. Our findings thus identify a group of proteins that are important for pre-mRNA processing as fusion partners for tyrosine kinases in hematological malignancies.
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PMID:The t(1;9)(p34;q34) and t(8;12)(p11;q15) fuse pre-mRNA processing proteins SFPQ (PSF) and CPSF6 to ABL and FGFR1. 1820 9

Pleomorphic lobular carcinomas (PLC) of the breast display histological features associated with classic invasive lobular carcinoma (ILC), yet they also exhibit more conspicuous nuclear atypia and pleomorphism, and an aggressive clinical behaviour. From a breast cancer progression perspective, it is unclear whether PLC is a variant of ILC or is a high-grade invasive ductal carcinoma (IDC) that has lost E-cadherin. The molecular features of 26 PLC were studied using immunohistochemistry [oestrogen receptor (ER), progesterone receptor (PR), HER2, p53 and E-cadherin], 0.9 Mb resolution, microarray-based comparative genomic hybridization (aCGH), fluorescent (FISH) and chromogenic (CISH) in situ hybridization and loss of heterozygosity. Comparative analysis was performed with aCGH data from PLC with classic ILC (16 cases) and high grade IDC (35 cases). PLCs were frequently ER- and PR-positive, E-cadherin-negative and occasionally HER2- and p53-positive. Recurrent copy number changes identified by aCGH included gains on 1q, 8q, 11q, 12q, 16p and 17q and losses on 8p, 11q, 13q, 16q and Xq. Highly recurrent 1q+ (100% of cases), 16p+ (93%), 11q- (53%) and 16q- (93%) and evidence of the der(1;16)/der(16)t(1;16) rearrangement, as detected by FISH, suggested that PLC had a 'lobular genotype'. Focal amplifications were evident at 8p12-p11, 8q24, 11q13.1-q14.1, 12q14, 17q12 and 20q13. Loss of BRCA2 was detected in 40% of PLC by LOH. Comparative analysis of aCGH data suggested the molecular features of PLC (ER/PR-positive, E-cadherin-negative, 1q+, 11q(-), 16p+ and 16q(-)) were more closely related to those of ILC than IDC, implicating an overlapping developmental pathway for these lobular tumour types. Molecular alterations found in PLC that are more typical of high-grade IDC than ILC (p53 and HER2 positivity, 8q+, 17q24-q25+, 13q(-) and amplification of 8q24, 12q14, 17q12 and 20q13) are likely to drive the high-grade and more aggressive biology of PLC.
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PMID:Molecular profiling pleomorphic lobular carcinomas of the breast: evidence for a common molecular genetic pathway with classic lobular carcinomas. 1847 30

Pure invasive micropapillary carcinoma (MPC) is a special histological type that accounts for 0.7-3% of all breast cancers. MPC has a distinctive growth pattern and a more aggressive clinical behaviour than invasive ductal carcinomas of no special type (IDC-NSTs). To define the molecular characteristics of MPCs, we profiled a series of 12 MPCs and 24 grade and oestrogen receptor (ER)-matched IDC-NSTs using high-resolution microarray comparative genomic hybridization (aCGH). In addition, we generated a tissue microarray containing a series of 24 MPCs and performed immunohistochemical analysis with ER, PR, Ki-67, HER2, CK5/6, CK14, CK17, EGFR, topoisomerase-IIalpha, cyclin D1, caveolin-1, E-cadherin, and beta-catenin antibodies. In situ hybridization probes were employed to evaluate the prevalence of amplification of HER2, TOP2A, EGFR, CCND1, MYC, ESR1, and FGFR1 genes. aCGH analysis demonstrated that MPCs significantly differed from IDC-NSTs at the genomic level. Gains of 1q, 2q, 4p, 6p, 6q23.2-q27, 7p, 7q, 8p, 8q, 9p, 10p, 11q, 12p, 12q, 16p, 17p, 17q, 19p, 20p, 20q, and 21q, and losses of 1p, 2p, 6q11.1-q16.3, 6q21-q22.1, 9p, 11p, 15q, and 19q were more prevalent in MPCs. High-level gains/amplifications of 8p12-p11, 8q12, 8q13, 8q21, 8q23, 8q24, 17q21, 17q23, and 20q13 were significantly associated with MPCs. A comparison between 24 MPCs and a series of 48 grade and ER-matched IDC-NSTs revealed that high cyclin D1 expression, high proliferation rates, and MYC (8q24) amplification were significantly associated with MPCs. Our results demonstrate that MPCs have distinct histological features and molecular genetic profiles supporting the contention that they constitute a distinct pathological entity.
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PMID:Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast. 1848 83

Owing to the heterogeneity of AML, the indication for allogeneic SCT (allo-SCT) requires an exact definition of the individual subentity and risk category. A comprehensive diagnostic approach is needed, which combines cytomorphology, cytogenetics, FISH, molecular genetics and immunophenotyping. Whereas the categorization in three prognostic karyotype groups is well established, rare recurrent aberrations as the unfavorable t(8;16)(p11;p13), inv(3)(q21q26) and t(6;9)(p23;q34) must also be considered. In normal karyotype, PCR analyses reveal prognostically relevant mutations in >85% of cases, and a molecular data set composed of the FLT3-ITD, MLL-PTD, NPM1 and CEBPA mutations was found able to guide the selection of patients for allo-SCT. Some novel markers as the WT1 mutations might further contribute to risk stratification in normal karyotype. The panel of minimal residual disease parameters is being expanded at this time, for example, by quantitative PCR for the NPM1 mutations. Immunophenotyping allows the definition of leukemia-associated phenotypes in nearly all cases, but its position in the indication to allo-SCT has to be validated. Thus, the optimization of the indication to allo-SCT is an ongoing process that should remain in continuous interaction with the increasing panel of known genetic markers and diagnostic methods.
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PMID:Interactive diagnostics in the indication to allogeneic SCT in AML. 1936 29


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