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)

The important advances made in recent years in the therapy of adult ALL have been reviewed. The definition of bad-prognosis patients has been improved and includes those with T-ALL, ABLL, and Ph1+ALL, in addition to those presenting with evidence of extensive disease. In contrast to childhood ALL, induction chemotherapy should include another drug (or drugs) in addition to VCR and prednisolone, and one of the anthracycline drugs (ADR or DNR) has been employed most frequently in this context. Such therapy should result in a CR rate of 70 to 75%. Similar to the experience in childhood ALL, the improvement in haematological response rate has led to an apparent increase in CNS leukaemia, and the need for adequate CNS prophylaxis is stressed. Despite these improvements, the outlook for adults with ALL is not yet as good as it is for childhood ALL. Controlled studies involving large numbers of patients are urgently needed to provide answers to a number of questions. In induction therapy, the use of higher drug dosage, the use of more and other drugs, and the use of an individual patient's risk factors to determine drug dosage, must be assessed. The benefits of consolidation therapy and the optimal duration and intensity of maintenance therapy have yet to be established. Methods of CNS prophylaxis other than cranial irradiation and IT MTX must be carefully studied. These important questions require that adult patients with ALL should be concentrated in centres capable of providing optimal overall care and, at the same time, able to conduct the necessary clinical trials.
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PMID:The management of adult acute lymphoblastic leukaemia. 36 95

The Philadelphia (Ph1) chromosome, or its molecular counterpart, the BCR-ABL fusion gene, is a rare but important prognostic indicator in childhood acute lymphoblastic leukemia (ALL), but its impact on adult ALL has not been well ascertained. A prospective study of the BCR-ABL fusion gene was begun on patients entered on clinical trials conducted by the Cancer and Leukemia Group B (CALGB). All patients received intensive, multiagent chemotherapy that included daunorubicin. Over 2 years, 56 patients were studied for molecular evidence of a BCR-ABL gene using Southern blot and pulsed-field gel hybridization analysis. Results were compared with cytogenetic detection of a Ph1 chromosome, and clinical features were compared for the BCR-ABL-positive and -negative groups. Molecular methods detected the BCR-ABL gene in 30% of cases compared with cytogenetic detection of the Ph1 chromosome in only 23%. The majority of cases (76%) showed the p190 gene subtype similar to pediatric ALL; the BCR-ABL-positive cases displayed a more homogeneous immunophenotype than the BCR-ABL-negative cases and were predominantly CALLA positive (86%) and B-cell surface antigen positive (82%). The rate of achieving complete remission was similar in the BCR-ABL-positive and -negative groups (71% and 77%, respectively, P = .72). There were more early relapses in the BCR-ABL-positive group, resulting in a shorter remission duration that was especially marked in the CALLA-positive and B-cell antigen-positive populations. These preliminary data suggest that the impact of the BCR-ABL gene on clinical outcome in ALL may be on maintenance of complete remission (CR) rather than achievement of CR when aggressive, multiagent chemotherapy is used. This study identifies the BCR-ABL gene as an important factor in adult ALL and demonstrates the utility of molecular methods for its accurate diagnosis.
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PMID:Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762). 146 14

The Philadelphia chromosome (Ph1) was the first genetic change to be associated consistently with leukemia, and it is one of the best understood on the molecular level. Because of this, it is an excellent model to investigate the application of molecular techniques to the clinical setting. These techniques are reviewed as are their clinical use in chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and transplantation. The Ph1 is caused by the fusion of two genes on chromosomes 9 and 22, resulting in the BCR-ABL fusion gene. This new gene is believed to be the cause of these Ph1-positive leukemias. The ability to detect the BCR-ABL fusion gene evolved from cytogenetic detection to Southern blot analysis, and now includes sophisticated techniques such as polymerase chain reaction (PCR) methods and pulsed-field gels. Diagnosis of the BCR-ABL fusion gene by Southern blot detection of bcr genetic rearrangements is the prototype of molecular cancer diagnosis. The sensitivity and clinical uses of this test are reviewed, especially its application to monitoring the response to treatment. PCR methods enable the researcher to detect 1 CML cell in a population of 10(5) cells. Clinical experience with PCR, especially in transplantation medicine, is providing a better understanding of the meaning of the terms "remission" and "cure." Newer techniques using fluorescent in situ hybridization have considerable potential for BCR-ABL detection, but no clinical experience has been gained with these techniques currently. The diagnosis of the BCR-ABL fusion gene in ALL has important clinical implications because it is the most common molecular genetic change in adult ALL and is associated with short remissions and poor outcome in all age groups. Diagnosis of the BCR-ABL fusion in ALL is difficult because the molecular findings are more heterogeneous than they are in CML. The methods available and their accuracy and sensitivity are compared. A review of their clinical impact is included.
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PMID:The role of molecular techniques in the clinical management of leukemia. Lessons from the Philadelphia chromosome. 151 23

The Philadelphia (Ph) translocation is the most common cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL) and is associated with an adverse prognosis. Using polymerase chain reaction (PCR) technology we recently observed a remarkably high incidence (55%) of BCR-ABL rearrangements in adult common ALL patients. In the present study we asked whether a subset of Ph-negative cALL, similarly to Ph-negative chronic myelocytic leukemia (CML) patients, exhibit BCR-ABL transcripts. PCR analysis of 58 adult Ph-negative cALL patients, including 47 cases with a normal karyotype revealed no evidence of chimeric BCR-ABL genes. We conclude that Ph-negative BCR/ABL-positive ALL is very rare entity if existing at all.
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PMID:Polymerase chain reaction analysis of BCR-ABL sequences in adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients. 159 11

The presence of Philadelphia chromosome t(9:22) is a hallmark of 95% of clinical cases of chronic myelogenous leukemia (CML) as well as 20% of adult acute lymphoblastic leukemia (ALL) and 5% of acute myeloid leukemia (AML). The product of t(9;22) is a fusion protein BCR-ABL. The fusion proteins of CML, ALL and AML have increased tyrosine kinase activity and show a transforming potential in vitro and in animal models. The shorter p190 protein is associated almost only with ALL and AML, while the protein p210 is present in both chronic phase and blast crisis of CML and also in 50% of Philadelphia-positive (Ph1+) ALL. In CML the transition from chronic phase to blast crisis is usually accompanied by additional genetic events, e.g. additional chromosomal abnormalities, and oncogene activation(s). The detailed understanding of molecular basis of CML, and Ph1+ ALL and AML provides highly sensitive molecular and serological methods to complement classical cytogenetics. The advantages and limitations of these techniques are described and discussed below.
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PMID:Molecular pathology of chronic myelogenous leukemia. 224 53

We report a case of adult acute lymphoblastic leukemia (ALL) with myeloid-like hypergranulation of blast cells. Like most of the "granular" ALLs described in the literature, the blast cells had L2 morphology and exhibited a common-ALL immunologic phenotype. The clinical findings at diagnosis were unremarkable. Cytogenetic analysis showed a 46XY karyotype. Molecular genetic analysis revealed T-cell receptor (TCR) gamma and immunoglobulin heavy chain rearrangements; no rearrangement was found at the TCR beta gene locus. The polymerase chain reaction (PCR) for the BCR-ABL translocation was negative. The clinical course of the patient was uncomplicated. On standard ALL treatment protocol he achieved complete remission (CR) within 4 weeks, and he is currently disease free 8 months after diagnosis. The case contributes well-documented data to the characterization of adult "granular" ALL, with special regard to changes at the molecular genetic level.
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PMID:Hypergranular acute lymphoblastic leukemia (ALL). Report of a case and review of the literature. 750 82

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

A subset of adult acute lymphoblastic leukemia (ALL) patients have blast cells which co-express myeloid-associated antigens (MY+ ALL). We have analyzed 113 adult ALL cases for expression of MY-associated antigens (MAA). ALL was diagnosed by standard morphology, cytochemistry, and immunophenotype in central review. MY+ ALL was diagnosed when > or = 20% of lymphoblasts co-expressed CD13 and/or CD33. Overall incidence of MY+ was 31/113 (27%). MAA expression was not significantly correlated with WBC, blast count, hemoglobin, or hematocrit. MY+ cases were more likely to express B-associated antigens, especially CALLA, and to be FAB L2, Ph+, or to have the BCR-ABL translocation by PCR, but these differences were not statistically significant. All patients were induced with a L10M regimen, and 67 (59%) achieved CR: 43/66 (65%) of B MY neg; 14/29 (48%) of B MY+; 10/16 (63%) T MY neg; and 0/2 T MY+. In age-adjusted analyses CR rate did not differ significantly between MY+ and MY neg patients or between B- and T-cell patients. Of the 113 patients, 84 have died and the remaining 29 patients have been followed for a median of 49 months. In proportional hazards regression analyses adjusting for age and WBC, heterogeneity of survival among the four groups was statistically significant (p = 0.021), largely due to MY status. The mortality rate was 85% greater for MY+ patients compared to MY neg patients (two-tailed p = 0.013). By contrast, survival did not vary significantly between B- and T-cell patients. The data indicate that MAA expression is useful for predicting overall survival of adult patients with ALL treated in a L10M protocol. As a predictive factor MAA expression is comparable to the WBC and superior to the more standard stratification by B- or T-cell markers for this group of patients.
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PMID:Expression of myeloid antigens by blast cells in acute lymphoblastic leukemia of adults. The Southwest Oncology Group experience. 780 99

The sensitivity and clinical utility of the polymerase chain reaction (PCR) assay for the detection of BCR-ABL gene rearrangement was compared to conventional cytogenetics for the Philadelphia chromosome (Ph1) in adult acute lymphoblastic leukemia (ALL) patients entered onto a single clinical trial. Ninety-three patients had evaluable PCR assays for both the p190bcr-abl and p210bcr-abl type of BCR-ABL gene rearrangements. Twenty-one of 93 patients (23%) were positive for the BCR-ABL rearrangement by the PCR assay. Fourteen of these patients had the p210brc-abl BCR-ABL rearrangement characteristically seen in CML patients, while seven had the p190bcr-abl rearrangement seen in ALL alone. Of 61 patients analyzed, both with conventional cytogenetics and PCR, eight (13%) were positive for the Ph1, while 14 (23%) were positive for the BCR-ABL rearrangement by the PCR assay. Discordance between the PCR assay and cytogenetics occurred in eight cases where the PCR assay was positive and the cytogenetics negative, and two cases where the PCR assay was negative and cytogenetics positive. PCR positivity did not correlate with treatment response, survival, or relapse-free survival, but there was a higher percentage of L2 FAB morphology in the PCR+ cases compared to the PCR-cases (67 vs. 28%, p = 0.003). In addition, the data suggested that patients with a p190bcr-abl rearrangement have a better response to induction therapy, but a worse relapse-free survival compared to patients with a p210bcr-abl breakpoint, but these differences were not statistically significant. These data suggest that PCR and conventional cytogenetics may provide complementary information, since there appear to be a subset of patients who are Ph1-negative yet BCR-ABL positive by PCR. Further studies will be required to determine the prognostic significance of the detailed information about BCR-ABL breakpoints that is available from the PCR assay.
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PMID:Detection of BCR-ABL fusion genes in adult acute lymphoblastic leukemia by the polymerase chain reaction. 793 64

The detection of BCR-ABL transcripts by polymerase chain reaction and hybridization protection assay was investigated in 59 adults with acute leukemia in whom the Philadelphia chromosome (Ph) abnormality was not documented by cytogenetic analysis. These included 35 patients with acute lymphocytic leukemia (ALL) and 24 with acute myelogenous leukemia (AML). Overall, three patients were found to have Ph-related molecular abnormalities; one had p190 and two had p210 disease. All three patients had ALL and were among 16 patients with insufficient metaphases by cytogenetic analysis, yielding an incidence of 19% in the latter category. Based on a 32% incidence of insufficient metaphases in our adult ALL population, we project an additional detection rate of 6% Ph-positive ALL by molecular studies and an overall incidence of 20% (14% + 6%) Ph-positive or BCR-ABL-positive ALL. None of the remaining patients with ALL and none of the 24 patients with AML investigated had BCR-ABL-positive disease. We conclude that molecular studies are useful in detecting BCR-ABL-positive disease in a subset of patients with Ph-positive ALL who are not identified by cytogenetic analysis because of insufficient metaphases.
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PMID:What is the contribution of molecular studies to the diagnosis of BCR-ABL-positive disease in adult acute leukemia? 810 97


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