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

Here we show that exposure of human B-cell precursors to gamma-rays stimulates the enzymatic activity of the Src protooncogene family protein tyrosine kinase LYN. LYN activation in irradiated cells is not triggered by DNA damage or a nuclear signal since gamma-rays effectively stimulated LYN kinase in enucleated B-cell precursors as well. LYN activation in irradiated cells was abrogated by presence of the OH* radical scavenger dimethylsulfoxide and exposure of intact or enucleated B-cell precursors to chemically generated OH* radicals instead of gamma-rays also triggered LYN kinase activation and enhanced tyrosine phosphorylation of multiple electrophoretically distinct protein substrates. Thus, OH* radicals appear to be both mandatory and sufficient for radiation-induced LYN kinase activation in irradiated B-cell precursors. We further present evidence which indicates that OH* radicals activate LYN by a novel mechanism which involves disruption of inactive LYN-LYN homodimers and monomerization of the LYN kinase after proteolytic degradation of a putative LYN-associated adapter protein through a cytoplasmic TPCK-sensitive chymotrypsin-like protease following its oxidation. LYN kinase plays a pivotal role in initiation of signal cascades that affect the proliferation, differentiation, and survival of B-cell precursors. Our results prompt the hypothesis that a growth regulatory balance might be altered in human B-cell precursors by radiation-induced stimulation of LYN kinase.
Leuk Lymphoma 1996 Aug
PMID:Role of hydroxyl radicals in radiation-induced activation of lyn tyrosine kinase in human B-cell precursors. 888 55

To determine if positron emission tomography (PET) imaging using F-18 fluorodeoxyglucose (FDG) can accurately distinguish between malignant and infectious central nervous system (CNS) mass lesions in patients with human immunodeficiency virus (HIV) infection, a prospective case series of 18 patients with HIV infection and focal CNS lesions on computed tomography (CT) or magnetic resonance (MR) scans was analysed. The patients were divided into 3 groups based on biopsy results, serology and response to therapy. Group 1 consisted of 8 patients with infectious lesions (4 with toxoplasmosis, 2 with neurosyphilis, 2 with progressive multifocal leukoencephalopathy (PML)). Group 2 consisted of 5 patients with biopsy proven CNS lymphoma. Group 3 consisted of 5 patients with presumed CNS lymphoma. Patients underwent FDG-PET studies as an adjunctive diagnostic procedure. The metabolic activity of each patient's lesion was graded using both a qualitative visual score and a semi-quantitative count ratio comparing the lesion with contralateral brain. CNS lesions diagnosed as lymphomas had statistically higher visual scores (P = 0.001) and count ratios (P = 0.002) than CNS lesions diagnosed as infections. FDG-PET could accurately differentiate lymphoma from infections in 16 of 18 cases. Two cases of PML had high metabolic activity and could not be differentiated from lymphoma. FDG-PET shows great promise in differentiating lymphoma from infectious lesions in the CNS of patients with HIV infection. If larger prospective studies confirm this impression, more specific and rapid treatment of CNS lesions could be performed and perhaps obviate the need for brain biopsy in many cases.
Int J STD AIDS
PMID:Differentiation of central nervous system lesions in AIDS patients using positron emission tomography (PET). 889 23

We have previously demonstrated that liposome-incorporated methylphosphonate antisense oligodeoxynucleotides (oligos) specific for BCR-ABL can selectively inhibit the expression of p210Bcr-Abl protein and the proliferation of chronic myelogenous leukemia cells in vitro. Here, we show that liposome-entrapment of phosphodiester and phosphorothioate oligos specific for BCR-ABL can also selectively inhibit the proliferation of chronic myelogenous leukemia cells. We have studied the intracellular localization of liposomes by fluorescent microscopy and found that liposomes are readily taken up by leukemic cells and are localized in the cytoplasm, allowing increased access of oligos to target cells intracellularly. Liposomal oligos are not toxic to peripheral blood mononuclear cells nor to bone marrow progenitors isolated from normal hematological donors. These studies strongly suggest that liposomal delivery of oligos may indeed circumvent the major limitations that preclude the clinical development of antisense oligos.
Leuk Lymphoma 1996 Mar
PMID:Liposomal delivery of oligodeoxynucleotides. 890 75

Seven secondary leukemia patients were treated for solid tumors or malignant lymphoma with anticancer drugs or radiation. We studied bone marrow samples from these patients by fluorescence in situ hybridization (FISH). Of the seven patients, three had increased signals for the ABL oncogene (9q34) on interphase nuclei and at metaphase. One of the three patients also had four signals for the CD3 (MLL) region (11q23). Whole painting probes revealed that these chromosomal regions were translocated onto structurally abnormal chromosomes, resulting in partial tri-, tetra- or penta-somy of these regions. We called this type of translocation "segmental jumping translocation (SJT)." SJT of the ABL oncogene was not detected in samples from 15 patients with de novo acute myelocytic leukemia (AML), 12 with myelodysplastic syndrome (MDS), or 20 with chronic myelocytic leukemia (CML) at the chronic phase. Furthermore, monosomy 7 was also found in the patients with the gene amplification. These results indicate that SJT of ABL and/or CD3 (MLL) genes is associated with the leukemogenesis of secondary leukemia. The SJT may be one mechanism of gene amplification.
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PMID:Frequent jumping translocations of chromosomal segments involving the ABL oncogene alone or in combination with CD3-MLL genes in secondary leukemias. 900 63

The ability of BCR-ABL oncoproteins to induce leukemic transformation of hematopoietic cells depends on their tyrosine kinase activity, which is essential for recruitment and activation of multiple pathways that transduce oncogenic signals. Although it is unknown yet whether activation of PI 3-kinase is required for transformation, the colony-forming ability of Philadelphia cells is dependent on PI 3-kinase activity, as indicated by the results of studies using a number of strategies to interfere with the synthesis and/or the function of the regulatory and catalytic subunits of this kinase. In particular, wortmannin, a specific PI 3-kinase inhibitor, preferentially affected colony formation of Philadelphia cells over that of normal marrow hematopoietic progenitors. The mechanism(s) of such effects are unknown, but PI 3-kinase inhibitors may represent a novel class of therapeutic agents for the ex vivo and/or in vivo treatment of Philadelphia leukemias.
Leuk Lymphoma 1996 Nov
PMID:BCR/ABL regulation of PI-3 kinase activity. 903 Oct 78

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.
Leuk Lymphoma 1996 Oct
PMID:ETV6 gene rearrangements in hematopoietic malignant disorders. 903 Nov 9

Bone marrow of 61 HIV-1-infected patients and 23 control patients was examined to determine the incidence of B19 infection and its clinical impact in HIV-1-infected persons. Of the 61 HIV-infected patients studied, ages ranged from 22-47 years with a mean of 33.2 years. There was a man:woman ratio of 3.8:1. With regard to staging of HIV disease at the time of bone marrow sampling, 52 patients were CDC group 4, 5 patients were CDC group 3, and 4 patients were CDC group 2. Control patients, were not known to be HIV-1-infected, and had one of the following conditions: lymphoma, leukaemia, thrombocytopenia, thrombocytosis, anaemia, multiple myeloma, raised serum IgM. Thirteen of 61 HIV-infected patients and 0 of 23 control patients were positive for B19 DNA in bone marrow (two-tailed P value = 0.016). Within the HIV-infected group, the average haemoglobin among persons testing B19 DNA positive (n = 13) was 11.1 g/dl, compared with 11.5 g/dl among persons testing B19 DNA negative (n = 48). In conclusion, B19 persistence may be common and frequently subclinical in AIDS patients.
Int J STD AIDS 1997 Mar
PMID:Parvovirus B19 infection in AIDS patients. 908 29

Over a time period of five years leukemic blast samples from 141 consecutive patients with adult ALL were referred to our laboratory, for molecular evaluation of chromosome abnormalities. The t(9;22), t(4;11) and t(1;19) which are most commonly found in adult ALL with a B-precursor phenotype were molecularly analyzed by similar RT-PCR based protocols. BCR-ABL transcripts generated by the t(9;22) translocation were demonstrated in 36 patients (25%) and were restricted to the 109 patients with B precursor ALL (33% of this group). Of 83 patients showing a, common phenotype (CD10+), 34 were BCR-ABL positive (41%) whereas only 2 out of 26 with Null ALL (HLADr+, CD19+, CD10) were positive. Interestingly, the percent of BCR-ABL positive CD1O+ ALL increases significantly with age being 20% in patients less than 30 years old and more than 50% in older patients. None of the T-ALL (24 patients) and B-ALL (8 patients) were positive. The majority of cases (67%) showed the p190 gene subtype. The cytogenetic diagnosis of Philadelphia chromosome was always confirmed by the molecular analysis and this approach allowed for the detection of the presence of the BCR-ABL rearrangement in 26 patients when a negative result or no metaphases were obtained. The complete remission rate was similar among BCR-ABL positive and negative patients but a shorter remission duration was observed in those showing molecular evidence of t(9;22) and this finding was significantly evident in CD1O+ ALL patients. By means of comparison, in most of the same adult ALL patients, we analyzed the yet unrecognized prevalence of the t(4;11) and t(1;19) translocations by the molecular analysis of their chromosomal breakpoints. Rearrangements of the ALL-1 gene on 11q23 band and ALL- l1AF.4 fusion transcripts specific for the t(4;11) were demonstrated in 7 out of the 21 Null ALL investigated, with no additional positive cases found among the other ALL subgroups. Overall the clinical behavior of t(4; 11) positive patients was dismal with a very short CR duration. Chimeric E2A-PBX1 transcripts generated by the t(1;19) were found in only two of the 87 B-precursor ALL analyzed. The presented results provide further evidence for the utility of RT-PCR based methods for the molecular diagnosis of chromosome translocations in ALL. The identification of such abnormalities can significantly contribute to the identification of more appropriate therapeutic options for standard and high risk ALL patients
Leuk Lymphoma 1996 May
PMID:Molecular diagnosis and clinical relevance of t(9;22), t(4;11) and t(1 ;19) chromosome abnormalities in a consecutive group of 141 adult patients with acute lymphoblastic leukemia. 917 11

The signal transduction pathway from heterotrimeric G proteins to the mitogen-activated protein kinase (MAPK) cascade is best understood in the yeast mating pheromone response, in which a serine/threonine protein kinase (STE20) serves as the critical linking component. Little is known in metazoans on how G proteins and the MAPK cascade are coupled. Here we provide genetic and biochemical evidence that a tyrosine kinase cascade bridges G proteins and the MAPK pathway in vertebrate cells. Targeted deletion of tyrosine kinase Csk in avian B lymphoma cells blocks the stimulation of MAPK by Gq-, but not Gi-, coupled receptors. In cells deficient in Bruton's tyrosine kinase (Btk), Gi-coupled receptors failed to activate MAPK, while Gq-coupled receptor-mediated stimulation is unaffected. Taken together with our previous data on tyrosine kinases Lyn and Syk, the Gq-coupled pathway requires tyrosine kinases Csk, Lyn, and Syk, while the Gi-coupled pathway requires tyrosine kinases Btk and Syk to feed into the MAPK cascade in these cells. The central role of Syk is further strengthened by data showing that Syk can bind to purified Lyn, Csk, or Btk.
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PMID:Genetic evidence for a tyrosine kinase cascade preceding the mitogen-activated protein kinase cascade in vertebrate G protein signaling. 920 44

We used reverse transcriptase polymerase chain reaction (RT-PCR) assays to examine primary leukemic cells in on-study diagnostic bone marrow specimens from 642 children with newly diagnosed acute lymphoblastic leukemia (ALL) for the expression of MLL-AF4, E2A-PBX1, and BCR-ABL fusion transcripts. All PCR assays were performed centrally in the Children's Cancer Group ALL Biology Reference Laboratory. MLL-AF4 transcript was found in only 0.7% of the study population which excluded infants. E2A-PBX1 transcript was found in 2.5% of the study population and 3.3% of B-precursor cases. Expression was associated with massive hepatomegaly. BCR-ABL transcript was found in 2.3% of cases and correlated with older age, induction failure, and inferior event-free survival (EFS). RT-PCR assays allow rapid identification of patients with MLL-AF4 and BCR-ABL positive ALL. These patients have a poor outcome with contemporary therapy and rapid identification facilitates timely allocation to innovative treatment programs.
Leuk Lymphoma 1997 Jun
PMID:Expression of BCR-ABL, E2A-PBX1, and MLL-AF4 fusion transcripts in newly diagnosed children with acute lymphoblastic leukemia: a Children's Cancer Group initiative. 925 Jul 88


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