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)

TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. We show here by co-immunoprecipitation and GST chromatography analyses that TEL and TEL-derived fusion proteins form homotypic oligomers in vitro and in vivo. Deletion mutagenesis identifies the TEL oligomerization domain as a 65 amino acid region which is conserved in a subset of the ETS proteins including ETS-1, ETS-2, FLI-1, ERG-2 and GABP alpha in vertebrates and PNTP2, YAN and ELG in Drosophila. TEL-induced oligomerization is shown to be essential for the constitutive activation of the protein kinase activity and mitogenic properties of TEL-platelet derived growth factor receptor beta (PDGFR beta), a fusion oncoprotein characteristic of the leukemic cells of chronic myelomonocytic leukemia harboring a t(5;12) chromosomal translocation. Swapping experiments in which the TEL oligomerization domain was exchanged by the homologous domains of representative vertebrate ETS proteins including ETS-1, ERG-2 and GABP alpha show that oligomerization is a specific property of the TEL amino-terminal conserved domain. These results indicate that the amino-terminal domain conserved in a subset of the ETS proteins has evolved to generate a specialized protein-protein interaction interface which is likely to be an important determinant of their specificity as transcriptional regulators.
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PMID:A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR beta oncoprotein. 900 69

Chromosomal abnormalities involving the short arm of chromosome 12 have been frequently observed in a broad spectrum of hematological malignancies. Recently, a gene located in this chromosomal region and implicated in leukemogenesis was identified. The gene, called ETV6 (previously known as TEL) is a new member of the ETS family, a group of genes thought to act as transcriptional activators. The gene spans 240 kb and consists of eight exons coding for a helix-loop-helix (HLH) and a DNA-binding domain. ETV6 was originally identified in a t(5;12)(q33;p13) occurring in a chronic myelomonocytic leukemia (CMML). Recent reports, however, show its involvement in a growing number of translocations associated with myeloid as well as lymphoid leukemias. At the molecular level fusions of ETV6 with PDGFRB (5q33), ABL (9q34), MNI(22q11) and AML1(21q22) have already been identified. Analysis of these chimeric proteins indicates that distinct domains of ETV6 can be involved in different fusion products, thus ETV6 can provide transcriptional and dimerization properties for partner genes, or the gene itself can act as an altered transcriptional factor. At least two clinico-pathological entities associated with ETV6 rearrangements have emerged as distinct disorders. The first one is a chronic myeloid malignancy characterized by t(5;12)(q33;p13), monocytosis and/or eosinophilia. The second entity is a type of childhood acute lymphoblastic leukemia (ALL) hallmarked by t(12;21)(p13;q22), and is shown to be the most frequent but cytogenetically largely undetectable chromosomal anomaly in childhood ALL.
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PMID:ETV6 gene rearrangements in hematopoietic malignant disorders. 903 Nov 9

Translocation t(5;12)(q33;p13), resulting in an ETV6/PDGFRB gene fusion, is a recurrent chromosomal abnormality associated with chronic myelomonocytic leukemia (CMML). An analogous translocation was also found in four cell lines with features of pre-B acute lymphoblastic leukemia (ALL). Using fluorescence in situ hybridization (FISH) we show here that in three of these cell lines identical complex rearrangements occurred. However, the regions involved on 5q and 12p are different from the breakpoints in CMML, and the translocation is accompanied by seemingly identical cryptic deletions of both 5q and 12p chromosome sequences in all analyzed pre-B ALL cell lines. The similar cytogenetic, FISH, and immunophenotyping findings in the three cell lines suggest that the t(5;12)(q31q33;p12) defines a new entity of pre-B ALL.
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PMID:A new subtype of pre-B acute lymphoblastic leukemia with t(5;12)(q31q33;p12), molecularly and cytogenetically distinct from t(5;12) in chronic myelomonocytic leukemia. 905 55

We have combined genetic, radiation-reduced somatic cell hybrid (RRH), fluorescent in situ hybridization (FISH), and physical mapping methods to generate a contig of overlapping YAC, PAC, and cosmid clones corresponding to > 3 continuous Mb in 11q13. A total of 15 STSs [7 genes (GSTP1, ACTN, PC, MLK3, FRA1, SEA, HNP36), 4 polymorphic loci (D11S807, D11S987, GSTP1, D11S913), 3 ESTs (D11S1956E, D11S951E, and W1-12191), and 1 anonymous STS (D11S703)], mapping to three independent RRH segregation groups, identified 26 YAC, 7 PAC, and 16 cosmid clones from the CGM, Roswell Park, CEPH Mark I, and CEPH MegaYAC YAC libraries, a 5 genome equivalent PAC library, and a chromosome II-specific cosmid library. Thirty-six Alu-PCR products derived from 10 anonymous bacteriophage lambda clones, a cosmid containing the polymorphic marker D11S460, or STS-positive YAC or cosmid clones were identified and used to screen selected libraries by hybridization, resulting in the identification of 19 additional clones. The integrity and relative position of a subset of clones was confirmed by FISH and were found to be consistent with the physical and RRH mapping results. The combination of STS and Alu-PCR-based approaches has proven to be successful in attaining contiguous cloned coverage in this very GC-rich region, thereby establishing for the first time the absolute order and distance between the markers: CEN-MLK3-(D11S1956E/D11S951E/W1-12191)-FRA1-D 11S460-SEA-HNP36/ D11S913-ACTN-PC-D11S703-GSTP1-D11S987-TEL.
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PMID:A 3-Mb contig from D11S987 to MLK3, a gene-rich region in 11q13. 926 7

Congenital (or infantile) fibrosarcoma (CFS) is a malignant tumour of fibroblasts that occurs in patients aged two years or younger. CFS is unique among human sarcomas in that it has an excellent prognosis and very low metastatic rate. CFS is histologically identical to adult-type fibrosarcoma (ATFS); however, ATFS is an aggressive malignancy of adults and older children that has a poor prognosis. We report a novel recurrent t(12;15)(p13;q25) rearrangement in CFS that may underlie the distinctive biological properties of this tumour. By cloning the chromosome breakpoints, we show that the rearrangement fuses the ETV6 (also known as TEL) gene from 12p13 with the 15q25 NTRK3 neurotrophin-3 receptor gene (also known as TRKC). Analysis of mRNA revealed the expression of ETV6-NTRK3 chimaeric transcripts in all three CFS tumours analysed. These were not detected in ATFS or infantile fibromatosis (IFB), a histologically similar but benign fibroblastic proliferation occurring in the same age-group as CFS. ETV6-NTRK3 fusion transcripts encode the helix-loop-helix (HLH) protein dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. Our studies indicate that a chimaeric PTK is expressed in CFS and this may contribute to oncogenesis by dysregulation of NTRK3 signal transduction pathways. Moreover, ETV6-NTRK3 gene fusions provide a potential diagnostic marker for CFS.
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PMID:A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. 946 53

Interleukin 3 (IL-3) and other hematopoietic cytokines transduce signals that stimulate DNA synthesis and cell survival. In certain chronic myelomonocytic leukemias, a TEL/platelet-derived growth factor receptor beta (PDGFRbeta) fusion protein is produced as a consequence of the t(5;12) translocation. It contains the amino terminus of the transcription factor TEL fused to the transmembranous and cytoplasmic domains of the PDGFRbeta. It is oncogenic as it substitutes for IL-3, thus promoting cell growth and preventing apoptotic cell death. The mechanism by which TEL/PDGFRbeta generates survival signals remains undefined. Here, we report that both IL-3 and TEL/PDGFRbeta initiate a signaling cascade that leads to the activation of the transcriptional factor NF-kappaB. In fact, either cytokine deprivation of IL-3-dependent Ba/F3 cells or exposure of TEL/PDGFRbeta-expressing cells to the specific inhibitor of the PDGFR tyrosine kinase, CGP53716, caused a strong decrease in NF-kappaB activity followed by extensive cell death. Further, treatment with the proteasome inhibitor Z-IE(O-t-Bu)A-leucinal suppressed IL-3 and TEL/PDGFRbeta-dependent survival. The same result was seen upon overexpression of an unphosphorylable form of IkappaBalpha. Because both conditions inactivate NF-kappaB by preventing its translocation into the nucleus, that process seems to be essential for cell survival in response to IL-3 and TEL/PDGFRbeta. Moreover, overexpression of a dominant-negative mutant of the protooncogene c-Myc, a downstream target of NF-kappaB, had a similar effect. We conclude that NF-kappaB plays an important role in maintaining cell survival in response to IL-3 and TEL/PDGFRbeta and that c-Myc may be a downstream effector mediating this effect.
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PMID:Evidence for a role of NF-kappaB in the survival of hematopoietic cells mediated by interleukin 3 and the oncogenic TEL/platelet-derived growth factor receptor beta fusion protein. 965 43

A large number of continuous human leukemia cell lines have been established over the last three decades. Clearly, leukemia cell lines have become important research tools. Here, we have summarized the immunological, molecular and standard cytogenetic features of a panel of well characterized B cell precursor (BCP)-leukemia cell lines which were derived from patients with acute lymphoblastic/undifferentiated leukemia (ALL/AUL) or chronic myeloid leukemia (CML) in blast crisis. Following the recently proposed immunological EGIL classification, we assigned our panel of 27 BCP-cell lines to one of the following categories: B-I pro-B cell line; B-II common-B cell line; and B-III pre-B cell line. All cell lines express general B-lineage associated surface markers (HLA-DR, CD22, CD79a) being negative for surface immunoglobulin (Ig); the differences between the subgroups reside in expression of CD10 and cytoplasmic Ig. Several BCP-cell lines show the myelomonocytic cell-associated markers CD13 and/or CD33. These immunologically 'biphenotypic' BCP-cell lines are generally TdT+ CD10+ CD13+ CD19+ CD22+ CD34+ and carry the Philadelphia (Ph) translocation. The BCP-cell lines display surface receptors for interferon-gamma (CD119), interleukin-7 (CD127) and FLT-3 ligand (CD135). All BCP-cell lines examined have complex numerical and structural chromosomal alterations including translocations commonly seen in BCP-ALL such as t(4;11), t(9;22), t(11;19), t(12;21), and t(17;19) involving the fusion genes MLL-AF4, BCR-ABL, ENL-MLL, TEL/ETV6-AML1 and E2A-HLF, respectively. Besides the expected rearrangement of the Ig heavy chain receptor gene, several cell lines also have rearrangements of the T cell receptor genes beta, gamma or delta. While some BCP-cell lines express (aberrantly) myeloperoxidase at the mRNA level, most lines are negative in the immunological or cytochemical staining. Several large series documented the difficulty in establishing such BCP cell lines with success rates in the range of 10-20% (on average 15%). Still, since the establishment of the first bonafide BCP-cell line in 1974 (cell line REH), some 150 cell lines have been established of which, however, only a small percentage have been sufficiently well characterized and described. A higher success rate for immortalizing any given leukemia cell might depend on a closer emulation of the physiological in vivo microenvironment. The possibility to grow in vitro leukemia cells at will would represent ideal experimental systems permitting basic research and patient-specific investigations. In summary, the use of well-characterized BCP-cell lines provide unprecedented opportunities for studying a multitude of biological aspects related to normal and neoplastic B-lymphocytes.
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PMID:Establishment and characterization of human B cell precursor-leukemia cell lines. 968 Jan 6

Morphological, cytogenetic, and biological evidence supports a relationship between congenital (infantile) fibrosarcoma (CFS) and congenital mesoblastic nephroma (CMN). These tumors have a very similar histological appearance, and they are both associated with polysomies for chromosomes 8, 11, 17, and 20. Recently, CFS was shown to contain a novel t(12; 15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. The aims of this study were to determine whether congenital mesoblastic nephroma contains the t(12;15)(p13;q25) translocation and ETV6-NTRK3 gene fusion and whether ETV6-NTRK3 fusions, in CMN and CFS, antedate acquisition of nonrandom chromosome polysomies. To address these aims, we evaluated 1) ETV6-NTRK3 fusion transcripts by reverse transcriptase polymerase chain reaction and sequence analysis, 2) genomic ETV6-region chromosomal rearrangement by fluorescence in situ hybridization, and 3) chromosomal polysomies by karyotyping and fluorescence in situ hybridization. We report ETV6-NTRK3 fusion transcripts and/or ETV6-region rearrangement in five of six CMNs and in five of five CFSs. The ETV6-NTRK3 fusion transcripts and/or ETV-region chromosome rearrangements were demonstrated in two CMNs and one CFS that lacked chromosome polysomies. These findings demonstrate that t(12;15) translocation, and the associated ETV6-NTRK3 fusion, can antedate acquisition of chromosome polysomies in CMN and CFS. CMN and CFS are pathogenetically related, and it is likely that they represent a single neoplastic entity, arising in either renal or soft tissue locations.
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PMID:Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. 981 36

Congenital mesoblastic nephroma (CMN) is an infantile spindle cell tumor of the kidney that is subdivided into "classical" and "cellular" forms based on the degree of cellularity and mitotic activity. The histogenesis of CMN remains obscure, but relationships to other pediatric renal neoplasms have been proposed. However, cellular CMN is virtually identical histologically to congenital fibrosarcoma (CFS), a malignant tumor of fibroblasts in children of the same age group. Moreover, cytogenetic studies have reported common trisomies in CFS and cellular CMN, particularly of chromosome 11. We show here that t(12;15)(p13;q25)-associated ETV6-NTRK3 gene fusions described in CFS are also present in cellular CMN. ETV6-NTRK3 chimeric transcripts were detected in 8 of 9 cellular CMNs and 2 of 2 mixed CMNs. In contrast, all of the four classical CMNs tested were negative, as were cases of Wilms' tumor and clear cell sarcoma of the kidney. Moreover, we found trisomy 11 only in cellular or mixed CMNs with the ETV6-NTRK3 gene fusion. Our studies indicate that classical and cellular CMN have different genetic features and support the concept that cellular CMN is histogenetically related to CFS. They also provide insight into potential mechanisms involved in the transformation of the classical into the cellular form of CMN.
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PMID:ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. 982 7

Chromosome translocations involving band 12p13 are known to be involved in a variety of hematologic malignancies, some of them resulting in rearrangement of the ETV6/TEL gene. Applying the fluorescence in situ hybridization (FISH) method, we found a cryptic translocation t(12;15)(p13;q25) in an adult acute myeloid leukemia (AML) patient. Hybridization with cosmid probes showed that the ETV6 gene was rearranged in this translocation. A patient-specific cDNA library was screened with ETV6 cDNA, and a novel fusion transcript was identified between the ETV6 and TRKC/NTRK3 gene located on 15q25. TRKC is a receptor tyrosine kinase that is activated by neurotrophin-3 (NT-3). It is known to be expressed broadly in neural tissues but not in hematologic cells, so far. ETV6-TRKC chimeric transcript encoded the pointed (PNT) domain of the ETV6 gene that fused to the protein-tyrosine kinase (PTK) domain of the TRKC gene. Two types of fusion transcript were determined, one that included the entire PTK domain of TRKC and the other in which the 3'-terminal 462 bp of TRKC was truncated within the PTK domain. Western blot analysis showed the expression of both chimeric proteins of 52 and 38 kD in size. Our results suggest that chimeric PTK expressed in the leukemic cells may contribute to cellular transformation by abnormally activating TRK signaling pathways. Moreover, this is the first report on truncated neurotrophin receptors associated in leukemia.
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PMID:Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25). 994 79


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