Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently identified a common ALL patient which harboured a chromosomal fusion between the TEL gene on chromosome 12 and the ABL gene on chromosome 9. We designed an RT-PCR assay to screen 186 adult ALL and 30 childhood ALL patients for this novel translocation. We were unable to identify any additional cases with a TEL/ABL fusion product.
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PMID:The fusion of TEL and ABL in human acute lymphoblastic leukaemia is a rare event. 778 92

In human leukemia, activation of the ABL proto-oncogene locus on chromosome 9 most commonly occurs as a result of its fusion to the BCR locus on chromosome 22. The resulting chimeric protein displays an elevated tyrosine kinase activity. We have identified a novel activation of ABL which involves a gene located on chromosome 12, designated TEL. Like BCR, TEL is fused in-frame with ABL and produces a fusion protein with an elevated tyrosine kinase activity when assayed in an immune complex. The amino-terminal sequences of TEL encode a helix-loop-helix motif which may mediate dimerization.
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PMID:The novel activation of ABL by fusion to an ets-related gene, TEL. 780 37

It has recently been shown that the t(12;21)(p13;q22) translocation fuses two genes, TEL on chromosome 12 and AML1 on chromosome 21. We have evaluated the frequency of this newly described translocation in acute lymphoblastic leukemia (ALL), and the feasibility of minimal residual disease (MRD) monitoring by polymerase chain reaction (PCR) amplification of TEL-AML1 transcripts. Thirty-nine adult- and 45 childhood-ALLs consecutively diagnosed in a single center were included in this study. TEL-AML1 fusion transcripts were searched for in the 39 adult- and 45 childhood-ALLs for which material was available. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were also studied by PCR in these cases. TEL-AML1 transcripts were found in 8 out of 35 (23%) childhood B-cell precursor ALLs (BCP-ALLs). TEL-AML1 transcripts were detected in only 1 of 31 adult BCP-ALLs (P = .04, Fisher's exact test). Nevertheless, in this adult case, TEL-AML1 transcripts were found at a low level in 2 of 3 different samples. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were found in 12, 3, and 1 cases of 31 adult BCP-ALLs, and in 1, 2, and 1 cases of 35 childhood BCP-ALLs, respectively. TEL-AML1 transcripts were never found associated with any other fusion transcripts. Taken together, the four types of chimeric transcripts were detected in 12 of 35 (34%) childhood BCP-ALL cases. No TEL-AML1 transcripts were detected in 11 T-cell ALLs (4 adults and 5 children), nor in 2 B-cell (slg+) ALLs. MRD was evaluated in 21 samples collected in 9 TEL-AML1+ childhood BCP-ALL cases during therapy (median follow-up = 200 days). Of 8 patients evaluated after induction therapy, 4 showed detectable but low levels of MRD. Of 7 patients serially evaluated, only one showed persistence of detectable MRD. This study shows that TEL-AML1 transcripts are frequently detected in pediatric BCP-ALLs and that these transcripts are molecular targets that will simplify the strategy of MRD monitoring in childhood BCP-ALL.
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PMID:TEL-AML1 fusion RNA as a new target to detect minimal residual disease in pediatric B-cell precursor acute lymphoblastic leukemia. 870 88

Cryptic t(12;21)(p12-13;q22) leading to TEL-AML1 fusion has recently been recognized as the most frequent genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) in Western countries. More recently, we found a similar frequency of this abnormality in Chinese children with ALL in Taiwan. In this study, we assessed further the frequency of TEL-AML1 fusion as well as that of BCR-ABL in Chinese adults with ALL, using reverse transcriptase-polymerase chain reaction assays. Among the 81 cases with newly diagnosed B lineage ALL studied, none had the TEL-AML1 fusion whereas 30 had the BCR-ABL fusion. The lack of cases with the TEL-AML1 fusion together with the high frequency of BCR-ABL fusion could largely account for the poorer outcome of adult ALL as compared with childhood ALL.
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PMID:Lack of TEL-AML1 fusion transcript resulting from a cryptic t(12;21) in adult B lineage acute lymphoblastic leukemia in Taiwan. 875 62

TEL is a member of the Ets family of transcription factors which are frequently rearranged in human leukemia. The mechanism of TEL-mediated transformation, however, is unknown. We report the cloning and characterization of a chromosomal translocation associated with acute myeloid leukemia which fuses TEL to the ABL tyrosine kinase. The TEL-ABL fusion confers growth factor-independent growth to the marine hematopoietic cell line Ba/F3 and transforms Rat-1 fibroblasts and primary murine bone marrow cells. TEL-ABL is constitutively tyrosine phosphorylated and localizes to the cytoskeleton. A TEL-ABL mutant containing an ABL kinase-inactivating mutation is not constitutively phosphorylated and is nontransforming but retains cytoskeletal localization. However, constitutive phosphorylation, cytoskeletal localization, and transformation are all dependent upon a highly conserved region of TEL termed the helix-loop-helix (HLH) domain. TEL-ABL formed HLH-dependent homo-oligomers in vitro, a process critical for tyrosine kinase activation. These experiments suggest that oligomerization of TEL-ABL mediated by the TEL HLH domain is required for tyrosine kinase activation, cytoskeletal localization, and transformation. These data also suggest that oligomerization of Ets proteins through the highly conserved HLH domain may represent a previously unrecognized phenomenon.
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PMID:Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. 875 9

The Philadelphia chromosome translocation generates a chimeric oncogene, BCR/ABL which causes chronic myelogenous leukemia. Two different fusion proteins can be produced, p190BCR/ABL and p210BCR/ABL, depending on the location of the breakpoint in BCR. Although the ABL tyrosine kinase activity of the resulting oncoprotein is essential for transformation, the exact functional contribution of BCR to transformation is unclear. A novel oncogene containing ABL is formed by the (9;12) translocation which fuses part of the ets-family member TEL to c-ABL in patients with acute leukemia. In an effort to compare the biological effects of various ABL oncogenes, we transformed two different factor-dependent murine hematopoietic cell lines with cDNA's encoding p210BCR/ABL, p190BCR/ABL, or TEL/ABL. Transfection of each of the three activated ABL oncogenes resulted in rapid emergence of growth factor-independence, and 2-4 sublines from each cell line with each oncogene were further studied. Each oncogene induced an increase in the tyrosine phosphorylation of cellular proteins and autophosphorylation of the oncoprotein itself. Overall, the pattern of increased tyrosine phosphorylation was similar in the cell lines, suggesting that many of the major substrates were identical. We specifically examined a series of proteins known to be p210BCR/ABL substrates, including rasGAP, Shc, SH-PTP2, SH-PTP1, CRK-L, CBL, paxillin, and STATs, and found that each were also tyrosine phosphorylated in response to p190BCR/ABL and TEL/ABL. These results suggest that the function of BCR can be largely replaced by the unrelated protein TEL with regards to transformation of murine hematopoietic cell lines to factor-independence, and support the hypothesis that a major contribution of both fusion partners is to activate the ABL tyrosine kinase.
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PMID:p210BCR/ABL, p190BCR/ABL, and TEL/ABL activate similar signal transduction pathways in hematopoietic cell lines. 880 88

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

The t(12:21) translocation fuses the TEL and AML1 genes and has been found in up to 28% of paediatric B-cell precursor acute lymphoblastic leukaemias (BCP-ALL). The AML1 gene is a transcription factor which regulates expression of several myeloid differentiation associated genes. A molecular analysis of TEL-AML1, E2A-PBX1, MLL-AF4, BCR-ABL expression and an immunophenotypic study of CD13/CD33 myeloid antigen expression have been performed prospectively on tumour cells from 96 paediatric BCP-ALL patients. Percentages of CD13 or CD33 expressing leukaemic cells were found to be higher in TEL-AML1 positive cases (n = 22) than in TEL-AML1 negative (n = 74) cases (P<0.001). In 22/96 cases (23%) >10% of neoplastic cells were found to express at least one of the two markers. In 14 of these cases (63%), TEL-AML1 expression was detected, whereas t(4;11), t(11;19) and t(9;22) translocations were found by molecular methods in only three cases (14%). In four cases (18%) no molecular marker was found. These data show that TEL-AML1 expression is significantly associated with myeloid antigen expression by leukaemic cells and suggests that the prognostic significance of myeloid antigen expression in paediatric ALLs should be re-evaluated in the light of molecular cytogenetic markers.
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PMID:The majority of myeloid-antigen-positive (My+) childhood B-cell precursor acute lymphoblastic leukaemias express TEL-AML1 fusion transcripts. 935 9

The Janus family of tyrosine kinases (JAK) plays an essential role in development and in coupling cytokine receptors to downstream intracellular signaling events. A t(9;12)(p24;p13) chromosomal translocation in a T cell childhood acute lymphoblastic leukemia patient was characterized and shown to fuse the 3' portion of JAK2 to the 5' region of TEL, a gene encoding a member of the ETS transcription factor family. The TEL-JAK2 fusion protein includes the catalytic domain of JAK2 and the TEL-specific oligomerization domain. TEL-induced oligomerization of TEL-JAK2 resulted in the constitutive activation of its tyrosine kinase activity and conferred cytokine-independent proliferation to the interleukin-3-dependent Ba/F3 hematopoietic cell line.
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PMID:A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. 936 Sep 30

A BCR/ABL-negative chronic myeloid leukemia (CML) with t(12;14) (p12;q11-13) as the sole chromosomal abnormality was investigated by fluorescence in situ hybridization (FISH), which disclosed a cryptic insertion of ETV6 (previously called TEL), located at 12p12, into ABL at chromosome band 9q34. ETV6/ABL fusion was confirmed by RT-PCR, revealing that the first five exons of ETV6 were fused in frame with ABL at exon 2. Wild-type ETV6 was expressed, in accordance with the FISH results showing no deletion of the second ETV6 allele. ETV6/ABL chimeric transcripts have previously been reported in acute leukemias, but never before in CML. The present case suggests that ETV6/ABL positivity may constitute a new genetic subgroup of BCR-negative CML.
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PMID:BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion. 936 38


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