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)

In four patients, the chromosome 9 breakpoint of the t(9; 22)(q34;q11) had occurred at different sites within an 8.25-kilobase (kb) region situated 5' of ABL exon 1B. Chromosome in situ hybridization and field inversion gel electrophoresis (FIGE) studies showed that ABL exons 1A and 1B were present on the Ph chromosome. Yet this large fusion gene produced an mRNA conventional for chronic myelogenous leukemia (CML). Splicing from BCR exon 3 to ABL exon 2 crossed more than 200 kb and deleted exons 1A and 1B. This breakpoint site may occur in about 10% of all CML patients. Three of our patients have pronounced thrombocytosis, and two had been diagnosed as having Ph-positive essential thrombocythemia. The platelet count of the other patient was not available.
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PMID:Entire ABL gene is joined with 5'-BCR in some patients with Philadelphia-positive leukemia. 186 41

A variant form of BCR/ABL junction was identified in a patient with chronic myelogenous leukaemia (CML). The BCR/ABL fusion mRNA of this patient showed in-frame junction between BCR exon c3 and ABL exon 2. Although the diagnosis of CML was made, the patient showed clinical features of essential thrombocythaemia (ET) rather than that of typical CML. Treatment with interferon-alpha showed no cytogenetic response. The c3-a2 type of BCR/ABL junction seems to be associated with elevated platelet count and thus could form a novel clinical entity different from typical CML.
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PMID:Elevated platelet count features the variant type of BCR/ABL junction in chronic myelogenous leukaemia. 875 98

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

The BCR-ABL hybrid gene, the main product of the t(9;22)(q34;q11) translocation, is found in the leukaemic clone of at least 95% of CML patients. The fusion protein encoded by BCR-ABL varies in size, depending on the breakpoint in the BCR gene. Three breakpoint cluster regions have been characterized to date: major (M-bcr), minor (m-bcr) and micro (mu-bcr). The overwhelming majority of CML patients have a p210 BCR-ABL gene (M-bcr), whose mRNA transcripts have a b3a2 and/or a b2a2 junction. There is apparently no significant difference between patients with a 5' or a 3' M-bcr breakpoint, except maybe for a slight predominance of b3a2-expressing cases among those with increased platelet counts (ET-like syndrome). The smallest of the fusion proteins, p190BCR-ABL, (m-bcr breakpoint) is principally associated with Ph-positive ALL. Rare cases of CML are due to a p190-type of BCR-ABL gene and, in these, the disease tends to have a prominent monocytic component, resembling CMML. CML resulting from a p230 BCR-ABL gene (mu-bcr breakpoint) is also rare, and has been associated with the CNL variant and/or with marked thrombocytosis. Exceptional CML cases have been described with BCR breakpoints outside the three defined cluster regions, or with unusual breakpoints in ABL resulting in BCR-ABL transcripts with b2a3 or b3a3 junctions, or with aberrant fusion transcripts containing variable lengths of intronic sequence inserts. The reciprocal ABL-BCR gene found in the derivative 9q+ chromosome of the t(9;22) is transcriptionally active in nearly two-thirds of CML patients but has not been shown so far to have a functional role in CML. 'Ph-negative CML' comprises cases of typical CML in whom the BCR-ABL gene can be detected by molecular methods and others who are genuinely BCR-ABL negative and usually have an atypical disease phenotype.
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PMID:BCR-ABL gene variants. 937 60

Philadelphia (Ph) chromosome-positive leukemias, with the bcr-abl gene translocation, have a dismal prognosis. The identification of Ph-positive patients is vitally important because only aggressive therapeutic approaches, such as allogeneic bone marrow transplantation, may result in long-term disease-free survival. Routine diagnostic methods, such as Southern blot analysis and cytogenetics, may lead to false-negative results. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis is considered the most sensitive tool for the detection of the bcr-abl translocation, and it is widely used alone or in combination with karyotyping or Southern blot analysis to identify Ph-positive cases. In this study, we used fluorescence in situ hybridization (FISH) with BCR and ABL double-color probes for detecting Ph-positive leukemias. The FISH results were compared with the results of cytogenetic and RT-PCR analyses in 75 patients with leukemia or other myeloproliferative syndromes (chronic myeloid leukemia, 30; acute lymphoblastic leukemia, 24; acute myelogenous leukemia, 6; essential (hemorrhagic) thrombocythemia, 12; chronic myelomonocytic leukemia, 2; and polycythemia vera, 1). FISH analysis proved to be simple, extremely reliable and sensitive; bcr-abl fusion detection was successful in the presence of all types of molecular junctions i.e., (b2a2, b3a2, and e1a2). Furthermore, a Ph-positive case that proved fusion negative by RT-PCR was identified as positive by FISH. The sensitivity of RT-PCR and FISH related to Ph-positive cases were 97% and 100%, respectively. Regarding specificity, in 4 (5%) of 75 patients, RT-PCR provided false-positive results. Cross-contamination was identified because a new specimen was harvested and reanalyzed when FISH, cytogenetics, and RT-PCR results were contradictory. We believe FISH is an optimal diagnostic method to detect bcr-abl translocation that can be used alone or to validate the results of RT-PCR analysis.
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PMID:A comparative analysis of FISH, RT-PCR, and cytogenetics for the diagnosis of bcr-abl-positive leukemias. 942 14

Reverse transcription polymerase chain reaction was used to detect an unusual BCR/ABL transcript in a patient who presented with thrombocythaemia and was Philadelphia chromosome positive but weakly reactive to conventional BCR/ABL fusion probes. Sequencing revealed the presence of a 12 bp insert between BCR exon2 (b2) and ABL exon2 (a2). In such cases the use of conventional BCR/ABL probes may lead to false negative results. This is the first report of this transcript. Clinically the patient has responded well to therapy.
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PMID:A novel BCR-ABL rearrangement in a Philadelphia chromosome-positive chronic myelogenous leukaemia variant with thrombocythaemia. 951 86

The pathogenesis of the increased number of megakaryocytes and thrombocytosis in essential thrombocythemia (ET) is still unknown. We examined the expression of c-mpl, a receptor of thrombopoietin (TPO), and its signaling molecules in a patient with ET. An 8-year-old girl showed a high platelet count and an increased number of bone marrow megakaryocytes. Neither chromosomal abnormalities nor myelofibrosis was observed. Following the diagnosis of ET, aspirin therapy was begun for the patient, with only modest improvement of symptoms. Her platelet count ranged from 1,200,000/microL to 2,200,000/microL for more than 2 years. In the analyses, the serum TPO level in the patient was 420 attomoles/mL (normal, 760 +/- 320). The level of c-mpl expression in bone marrow mononuclear cells was higher in the patient than in healthy children, while there was no difference in the level of c-mpl expression in CD34+ cells, indicating an expanded pool of megakaryocytic lineage cells. The level of Janus kinase 2 (Jak2) expression was lower in the patient than in a healthy child. These findings indicate that the signal pathway mediated by c-Mpl after binding to TPO may be impaired in ET. Further analysis is needed to clarify the mechanism underlying the development of thrombocytosis in ET patients.
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PMID:Analysis of thrombopoietin and c-mpl expression in a child with essential thrombocythemia. 965 38

Constitutive tyrosine phosphorylation of CrkL was recently demonstrated in platelets from chronic myelogenous leukaemia (CML) patients but BCR-ABL tyrosine kinase could not be detected in the platelet lysates. We studied platelets from 14 CML patients with different types of BCR-ABL mRNA and with maximal platelet counts ranging from 149 to 3069 x 10(9)/l. P210BCR-ABL protein was detected by Western blotting in platelet lysates of 12/13 CML patients with active disease but not in the lysate of platelets from a Ph-positive acute lymphoblastic leukaemia (ALL) patient in remission or eight BCR-ABL-negative controls including one essential thrombocythaemia (ET) patient. Immunoblotting of p210BCR-ABL-positive platelets lysates with anti-CrkL antibody revealed a CrkL triplet consisting of one unphosphorylated and two phosphorylated forms of the protein. This CrkL phosphorylation pattern was not observed in normal platelets or CML platelets treated with ABL tyrosine kinase inhibitor CGP57148B. The presence of BCR-ABL provides an explanation for the constitutive tyrosine phosphorylation of CrkL in CML platelets. As no correlation was observed between platelet counts and platelet BCR-ABL protein expression, thrombocytosis or thrombocythaemia in CML cannot be explained by constitutive BCR-ABL-mediated CrkL tyrosine phosphorylation.
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PMID:BCR-ABL oncoprotein is expressed by platelets from CML patients and associated with a special pattern of CrkL phosphorylation. 988 28

A case history is reported here in which leukocytosis, thrombocytosis and hypercalcemia associated with rapidly relapsing squamous cell carcinoma (SCC) of the renal pelvis were observed. In a 58-year-old man, SCC of the renal pelvis was documented during nephrolithotomy, and right nephrectomy was performed. Local relapse of the tumor occurred rapidly in 2 months' time and hypercalcemia, leukocytosis and thrombocytosis worsened in accordance with tumor volume. Cranial computerized tomography (CT), thorax CT and bone scintigraphy were negative for metastasis. The serum parathyroid hormone level was 28 pg/ml (normal 9- 55 pg/ml). To disclose leukocytosis and thrombocytosis, peripheral smear and bone marrow aspiration were performed and no pathologic finding regarding any hematologic disorder was found; the samples were also BCR-ABL negative and Philadelphia chromosome negative. Production of several factors by tumor cells may be responsible for this paraneoplastic syndrome. The association of SCC of the renal pelvis with this triple paraneoplastic syndrome is an extremely rare occurrence.
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PMID:Rapidly relapsing squamous cell carcinoma of the renal pelvis associated with paraneoplastic syndromes of leukocytosis, thrombocytosis and hypercalcemia. 1149 Feb 18

Essential thrombocythemia (ET) is a chronic myeloid disorder that is characterized by thrombocytosis, thrombohemorrhagic and vasomotor symptoms, a long median survival, and a low risk of transformation to leukemia. ET can be difficult to distinguish from secondary (reactive) thrombocytosis, and the diagnosis of ET can only be made after the exclusion of other marrow disorders with similar features. Although ET has been assumed to be a clonal process, recent studies have suggested that a substantial number of cases classified as ET may actually not be clonal, and nonclonality may be associated with a lower risk of thrombosis. The lack of a characteristic cytogenetic marker for ET confounds analyses of clonality and offers no insight into disease pathogenesis. There is controversy over the proper classification of thrombocytosis associated with the pathological BCR-ABL gene rearrangement; such cases are not clearly distinguishable from chronic myelogenous leukemia (CML) and should be provisionally classified as CML. New insights are emerging into the role of the megakaryocytopoiesis regulator thrombopoietin (TPO) and its receptor, c-Mpl, in ET and related disorders, but TPO-Mpl dynamics appear to be complex. In some familial thrombocythemic syndromes, mutations in the 5' untranslated region of TPO have recently been described, but these have not yet been observed in sporadic ET. In the future, global analysis of gene expression patterns may help overcome diagnostic dilemmas, refine disease classification, and lead to an improved understanding of the pathogenesis of ET.
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PMID:Cytogenetic and molecular genetic aspects of essential thrombocythemia. 1218 22


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