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:2.7.10.2 (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

Interferon alfa has been used in the treatment of myeloproliferative disorders, particularly chronic myeloid leukemia, polycythemia vera, and idiopathic thrombocythemia. The effectiveness of interferon alfa in agnogenic myeloid metaplasia needs additional evaluation, although preliminary evidence suggests that it may be more efficacious when used in the cellular (ie, proliferative) phase than when the marrow is fibrotic or osteosclerotic. Cytogenetic and molecular changes after interferon alfa therapy are apparent in patients with chronic myeloid leukemia, as manifested by change in the Philadelphia chromosome and BCR-ABL gene, respectively. The exact role of interferon in prolonging the life of chronic myeloid leukemia patients, however, remains to be determined in larger studies of longer duration. Interferon treatment seems to be well tolerated, and the frequency of treatment-limiting toxicity is low. Data to date suggest that interferon alfa may be a new and effective drug for the treatment of the myeloproliferative disorders.
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PMID:Interferon in the treatment of myeloproliferative diseases. 211 94

The Philadelphia (Ph) chromosome usually results from the t(9;22), which causes the physical association of the BCR1 and ABL genes and their function as a single new gene. This precise genomic mutation probably has a significant role in the development of leukemia in humans, but that leukemia may take several forms: chronic myeloid leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, and essential thrombocythemia; CML also transforms to a lymphoid or myeloid acute phase. Two models are considered with regard to determinants of this variable hematologic expression of BCR-ABL. The first is variation in the breakpoint site of BCR1. Two breakpoint sites, M-BCR and m-BCR, are known, and their occurrence shows a nonrandom association with the different forms of leukemia. The precise position of the breakpoint within M-BCR may also be important. The second model concerns the role of other genes in determining the leukemic form shown by BCR-ABL. Results are reviewed of a patient who entered blast crisis CML and whose leukemic clones involved ten genetic loci with known leukemic associations. Many of these were probably genetic variants that allowed leukemic proliferations following the initiation of blast crisis. The multiplicity of these genes may obscure the prime determinant of blast crisis, which is unknown at the present time.
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PMID:The variable hematologic expression of the BCR-ABL genomic mutation and its possible determinants. 279 Jul 50

Much of our understanding of the molecular anomalies involved in the process of oncogenesis has resulted from research into malignant hematologic diseases, facilitated by the accessibility of hematopoietic cells. For example, in lymphoid tumors, rearrangement of the genomic DNA can lead to the juxtaposition of proto-oncogenes and the highly active sequences regulating synthesis of immunoglobulins or T-cell receptors. The subsequent malignancy results from an uncontrolled overexpression of a normal protein. This type of "quantitative" anomaly occurs in follicular lymphomas where B-cells overexpress the normal BCL2 protein which inhibits apoptosis, contributing to immortalization of the B done. The same type of rearrangement process can approach gene fragments which fusion and lead to production of a highly oncogenic chimerical or truncated abnormal protein. Such "qualitative" anomalies occur in myeloid hemopathies. Both types of anomalies involve genes controlling the cell cycle, cell differentiation or cell death (apoptosis), in particular transcription factors (for example, E2A, RARA, MYC) and molecules involved in signal transduction (for example RAS, ABL, LCK). A molecular anomaly can be detected in approximately 30% of all cases of acute leukemia and in up to 75% of the non-Hodgkin lymphomas. Analysis of the junction fragments of the different heavy chains of the immunoglobulins produced in these cases provides a specific marker for detecting the B or T-cell clone in digestive or skin biopsies. For example, detection of a BCR-ABL transcript in a patient with primary thrombocythemia or an atypical myeloproliferative syndrome can be diagnostic and detection of the donal immunoglobulin or T-cell receptor rearrangement can confirm the malignant nature of the lymphoid proliferation. Molecular markers also have prognostic value allowing patient stratification and more adapted therapy. Molecular anomalies detected in malignant hematologic diseases are thus examples of nearly perfect "tumor-specific" markers.
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PMID:[Molecular anomalies in malignant hemopathies]. 923 51

One of the diagnostic criteria of essential thrombocythemia (ET) is the absence of the Philadelphia chromosome (Ph-neg). On the molecular level, Ph-neg ET patients may carry BCR-ABL transcript. The natural history of BCR-ABL positive Ph-neg ET patients is undetermined. We examined the BCR-ABL status by reverse transcriptase two-step nested polymerase chain reaction in bone marrow aspirates of 25 Ph-neg ET patients. We found 12 BCR-ABL positive and 13 BCR-ABL negative patients in the study group. The comparison showed that the two groups had similar clinical and laboratory characteristics, except for a significant increased patients' age and decreased polymorphonuclear cell count in the BCR-ABL positive group. During a median follow-up of 20 and 22.5 months for the BCR-ABL negative and positive groups, respectively, there was neither blastic transformation nor unrelated death in both groups. We conclude that it is important to look for BCR-ABL transcript in Ph-neg ET patients and to follow them closely to investigate the nature of this translocation in this group of patients.
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PMID:BCR-ABL transcripts in bone marrow aspirates of Philadelphia-negative essential thrombocytopenia patients: clinical presentation. 1156 40

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

Philadelphia-negative (Ph-neg) essential thrombocythemia (ET), polycythemia vera (PV) and idiopathic myelofibrosis (IMF) form a syndrome of related chronic myeloproliferative disorders (MPD) characterized by expansion of one or more of the hematopoietic progenitors. Based on our previous finding of BCR-ABL transcripts in bone marrow aspirates of 12/25 Ph-neg ET patients, we have expanded our study up to 40 patients. Here we describe the rational for performing this study and report 19 of 40 patients who have BCR-ABL transcripts in their BM, 11 of them carry b3a2 and 8 carry b2a2. The two groups, BCR-ABL positive and negative, were completely identical with regard to clinical characteristics and laboratory data. We also report preliminary results of our attempt to examine concordance or discordance of BCR-ABL expression in the peripheral blood and bone marrow of Ph-neg ET patients.
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PMID:Significance of BCR-ABL transcripts in bone marrow aspirates of Philadelphia-negative essential thrombocythemia patients. 1019 23

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterised by the absence of the Philadelphia (Ph+) chromosome. Recent studies have reported controversial results relating to BCR-ABL rearrangements in ET patients. We studied 44 Ph-negative ET patients with the RT-PCR technique at diagnosis or during the follow-up. None of them showed any of the BCR-ABL transcript actually described by others in ET; neither the "classical" P210 nor the P190 or P230 variants. Our results confirm the absence of BCR-ABL abnormalities in Ph-negative ET patients.
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PMID:Screening of Bcr-Abl transcripts in Philadelphia negative essential thrombocythemia. 1134 14

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

Mutations that deregulate proliferation and survival pathways have emerged as a common molecular theme in the pathogenesis of myeloproliferative disorders (MPDs). Three studies now report an amino acid substitution in the JAK2 kinase in most patients with polycythemia vera as well as in some cases of essential thrombocythemia and chronic idiopathic myelofibrosis. Functional analysis demonstrates that this mutation confers erythropoietin-independent growth in vitro, deregulates signaling pathways downstream of JAK2, and causes polycythemia in mice. These results open new avenues for diagnosing and classifying patients with these disorders, and identify a new molecular target for drug discovery.
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PMID:JAKing up hematopoietic proliferation. 1583 17


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