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)

We investigated the significance of p185BCR/ABL expression in patients with chronic myelogenous leukaemia (CML) in relation to disease features, therapy and outcome. Results of Western blot analysis for 1384 patients referred with a diagnosis of CML to our institution from 1989 to 1997 were reviewed. Clinical characteristics, results of cytogenetic analysis and RT-PCR for BCR rearrangement were analysed. Five patients with Ph-positive CML expressing the p185BCR/ABL hybrid protein were identified. By RT-PCR, bone marrow specimens of these patients were confirmed to have an e1a2 junction. The median age at diagnosis of these patients was 55 years (range 43-76). All had elevated white cell counts at diagnosis (median 50 x 109/l, range 11.7-163 x 109/l). Four patients had monocytosis (range 10-16%) with a low neutrophil/monocyte ratio in the peripheral blood (range 3.4-5.7). Patients presented with various stages of the disease (two in chronic-phase CP, two in accelerated-phase AP, and one in blastic-phase BP). The clinical course and therapy of the patients varied, with one patient receiving hydroxyurea only, three patients receiving hydroxyurea followed by interferon-alpha based regimens and bone marrow transplantation. The patient presenting in BP was treated with combination chemotherapy. The clinical outcome of the patients was also varied with one patient alive and in complete remission (with complete cytogenetic remission after transplant) and four patients dead after progression to more advanced stages. We conclude that patients with Ph-positive p185BCR/ABL CML frequently present with monocytosis and a low neutrophil/monocyte ratio in the peripheral blood, aiding the speculation that the presence of the p185BCR/ABL hybrid protein may contribute to a phenotype intermediate between CML and CMML. Of interest, the only other specific clinical feature identified was the absence of splenomegaly in four of five patients. There was no definite association with transformation to lymphoid blast phase.
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PMID:Chronic myelogenous leukaemia with p185(BCR/ABL) expression: characteristics and clinical significance. 1058 63

We have developed a rapid real-time quantitative PCR method for measuring BCR-ABL mRNA levels in peripheral blood in chronic myeloid leukaemia (CML). The technique was used to monitor minimal residual disease for the early detection of relapse and as an assessment of treatment response. Normal BCR mRNA was quantitated to control for RNA degradation and the results reported as a percentage of BCR-ABL/BCR. Every patient measured at diagnosis (n = 21) had increased expression of BCR-ABL of up to 5-fold above the normal BCR levels. With effective treatment the BCR-ABL levels decreased. The molecular data was correlated with Philadelphia chromosome levels in bone marrow and a good correlation was found when treatment induced a cytogenetic response (Spearman correlation = 0.94, P < 0.0001, n = 67 samples). In patients receiving interferon-alpha therapy we found a significant difference in the BCR-ABL levels between cytogenetic response groups. The method was sensitive, reproducible, and readily detected a change in BCR-ABL transcript levels in serial blood samples. Sample throughput was high because post PCR processing was unnecessary. We conclude that real-time quantitative PCR monitoring of peripheral blood can be used to reliably monitor disease response in CML.
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PMID:Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. 1058 64

A substantial minority of patients with chronic myelogenous leukemia (CML) achieve a complete response (CR) to treatment with interferon-alpha (IFN), defined as the disappearance of Philadelphia chromosome-positive metaphases. Currently it is unclear how long IFN treatment should be continued for such patients. We used a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to quantify levels of BCR-ABL transcripts in 297 peripheral blood specimens collected from 54 patients who had achieved CR with IFN. The median duration of observation was 1.9 years (range, 0.3-11.0 years). Total ABL transcripts were quantified as internal control and results were expressed as the ratio BCR-ABL/ABL. All 54 patients had molecular evidence of residual disease, although 3 patients were intermittently PCR negative. The median BCR-ABL/ABL ratio at the time of maximal response for each patient was 0.045% (range, 0%-3. 6%). During the period of observation 14 patients relapsed, 11 cytogenetically to chronic phase disease and 3 directly to blastic phase. The median ratio of BCR-ABL/ABL at maximal response was significantly higher in patients who relapsed than in those who remained in CR (0.49% versus 0.021%, P < 0.0001). Our findings show that the level of residual disease falls with time in complete responders to IFN, but molecular evidence of disease is rarely if ever eliminated. The actual level of minimal residual disease correlates with the probability of relapse. We suggest that for patients who reach CR, IFN should be continued at least until relatively low levels of residual leukemia are achieved. (Blood. 2000;95:62-66)
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PMID:Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Group. 1060 85

In recent years, the prognosis of chronic myeloid leukemia (CML) has been greatly improved either with interferon-alpha (IFN-alpha) therapy or allogeneic bone marrow transplantation (BMT). In the present study, minimal residual disease was evaluated in 21 patients in complete cytogenetic response (CCR) after such treatments. Samples from bone marrow aspirates or peripheral blood or both were analyzed by conventional cytogenetics, Southern blot, interphase fluorescent in situ hybridization (FISH), and quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR). In all patients, FISH detected 1% to 12% nuclei with a BCR-ABL fusion gene, whereas Q-RT-PCR experiments were negative or weakly positive. Based on these results, we hypothesize that the BCR-ABL genomic rearrangement persists unexpressed in nonproliferating cells whatever the treatment (IFN-alpha or BMT). These data point to the need for follow-up of CML patients in CCR over an extensive period at the DNA level (FISH) to evaluate the residual disease and at the RNA level (Q-RT-PCR) to estimate the risk of relapse. (Blood. 2000;95:404-408)
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PMID:Persistence of BCR-ABL genomic rearrangement in chronic myeloid leukemia patients in complete and sustained cytogenetic remission after interferon-alpha therapy or allogeneic bone marrow transplantation. 1062 42

The degree of tumor load reduction after therapy is an important prognostic factor for patients with CML. Conventional metaphase analysis has been considered to be the 'gold standard' for evaluating patient response to treatment but this technique normally requires bone marrow aspiration and is therefore invasive. The frequency of cytogenetic analyses can be considerably reduced if patients are also monitored by molecular methods, which can be performed on peripheral blood specimens. Of the various techniques available, most attention has been paid to RT-PCR for BCR-ABL mRNA since this is by far the most sensitive. Simple, non-quantitative RT-PCR analysis gives only limited information on patients after treatment. Quantitative RT-PCR assays have been developed to monitor the kinetics of residual BCR-ABL transcripts over time. Variables in the quantitative PCR assay may be controlled for by quantification of transcripts of a normal gene (eg ABL or glucose-6-phosphate dehydrogenase, G6PD) as an internal standard. After allogeneic stem cell transplantation, most patients become RT-PCR negative, often after a period of low level positivity that may persist for several months. Those patients destined to relapse are characterized by the reappearance and/or rising levels of BCR-ABL transcripts. In contrast, for patients treated with interferon-alpha (IFN) residual disease is rarely, if ever, eliminated. The actual level of minimal residual disease in complete cytogenetic responders to IFN correlates with the probability of relapse. New quantitative real time procedures promise to simplify the protocols that are currently in use, but standardization and the introduction of rigorous, internationally accepted controls are required to enable RT-PCR to become a robust and routine basis for therapeutic decisions.
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PMID:Detection and quantification of residual disease in chronic myelogenous leukemia. 1086 64

We report the previously undescribed occurrence of extramedullary blast crisis in a patient with chronic myelogenous leukemia in complete cytogenetic and molecular remission on interferon-alpha. Development of bilateral testicular swelling prompted a biopsy showing stromal infiltration with CD20 and TdT positive immature cells. On repeated examinations, the bone marrow remained BCR/ABL negative by RT-PCR analysis. However, the cerebrospinal fluid (CSF) contained atypical lymphocytes positive for the P210 BCR-ABL product. Following treatment with testicular irradiation, intrathecal methotrexate, systemic chemotherapy and an unrelated donor transplant, the patient showed no evidence of disease until 9 months post-transplant, when he relapsed in lymphoid blast crisis in both bone marrow and CSF.
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PMID:Extramedullary blast crisis in a patient with chronic myelogenous leukemia in complete cytogenetic and molecular remission on interferon-alpha therapy. 1093 25

The use of the real-time reverse-transcription polymerase-chain reaction (RT-PCR) method to quantify BCR-ABL transcripts before and after allogeneic transplant was prospectively studied in 65 patients with chronic myeloid leukemia (CML). The expression of the BCR-ABL transcript was determined and normalized using the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) housekeeping gene product as an endogenous reference. In the single step real-time PCR assay, tenfold serial dilutions of cDNA of the K5652 cell line remained positive down to 100 pg cDNA only. However, molecular relapses of CML after transplant were only safely detectable when a nested real-time PCR assay was performed, which was able to detect 1-10 pg cDNA from a tenfold serial dilution. The median normalized BCR-ABL transcript level was measured as 0.004% in 17 patients with a molecular relapse, 0.4% in 7 patients with a cytogenetic relapse, 2.6% in 36 patients with a stable phase of CML, and 36% in 5 patients with a relapse in a blast crisis. The analyzed median normalized amount of BCR-ABL transcript differed significantly (P<0.001) between the various disease stages. In ten CML patients with relapse, the real-time PCR method was used to monitor the response of various immunotherapies as donor leukocyte infusions, withdrawal of immunosuppression, or interferon-alpha application. The results of the quantitative evaluation of BCR-ABL transcripts reflected very well the clinical effect of the different applied immunotherapies. The new real-time PCR method seems to be a suitable technique for the early detection of relapse after allogeneic transplant in patients with the BCR-ABL transcript. Its ability to distinguish between molecular and cytogenetic relapse (P<0.001) allows early therapeutic decisions.
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PMID:The amount of BCR-ABL fusion transcripts detected by the real-time quantitative polymerase chain reaction method in patients with Philadelphia chromosome positive chronic myeloid leukemia correlates with the disease stage. 1098 61

A multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) assay for both major forms of BCR-ABL was compared with fluorescence in situ hybridization (FISH), karyotyping, and Southern blotting for disease monitoring in 37 follow-up bone marrow samples from 32 patients with Ph1-positive leukemia. Of these 37 samples, 33 were from patients with chronic myeloid leukemia (CML) (26 post allogeneic bone marrow transplantation [AlloBMT] and seven during interferon-alpha therapy) and 4 from Ph1-positive acute lymphoblastic leukemia (ALL) patients (1 post AlloBMT and 3 post high dose chemotherapy). For the 27 samples studied after AlloBMT (26 CML and 1 Ph1-positive ALL) the time after transplantation ranged from 1 to 107 months (median 47.5 months). In 8 (22%) of the 37 samples there were discrepant results among methods. The discrepancy rates relative to other techniques were: karyotyping 17% (5 of 29), Southern blotting 18% (6 of 33), multiplex RT-PCR 8% (3 of 37), and FISH 8% (3 of 37). Therefore, the relative accuracy of each method for disease monitoring in Ph1-positive leukemia was: 83% (24 of 29) for karyotyping, 82% (27 of 33) for Southern blotting, 92% (34 of 37) for FISH, and 92% (34 of 37) for multiplex RT-PCR. This multiplex RT-PCR assay appears equivalent to FISH in terms of accuracy, simplicity, and turnaround time and both are superior to Southern blot and conventional cytogenetics in the laboratory monitoring of Ph1-positive leukemias.
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PMID:Comparison of a multiplex reverse transcriptase-polymerase chain reaction for BCR-ABL to fluorescence in situ hybridization, Southern blotting, and conventional cytogenetics in the monitoring of patients with Ph1-positive leukemias. 1112 44

We have previously shown that interferon-alpha (IFN alpha)-dependent tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) is impaired by serine phosphorylation of IRS-1 due to the reduced ability of serine phosphorylated IRS-1 to serve as a substrate for Janus kinase 1 (JAK1). Here we report that FKBP12-rapamycin-associated protein (FRAP) is a physiologic IRS-1 kinase that blocks IFN alpha signaling by serine phosphorylating IRS-1. We found that both FRAP and insulin-activated p70 S6 kinase (p70(s6k)) serine phosphorylated IRS-1 between residues 511 and 772 (IRS-1(511-772)). Importantly, only FRAP-dependent IRS-1(511-772) serine phosphorylation inhibited by 50% subsequent JAK1-dependent tyrosine phosphorylation of IRS-1. Furthermore, treatment of U266 cells with the FRAP inhibitor rapamycin increased IFN alpha-dependent tyrosine phosphorylation by twofold while reducing constitutive IRS-1 serine phosphorylation within S/T-P motifs by 80%. Taken together, these data indicate that FRAP, but not p70(s6k), is a likely physiologic IRS-1 serine kinase that negatively regulates JAK1-dependent IRS-1 tyrosine phosphorylation and suggests that FRAP may modulate IRS-dependent cytokine signaling.
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PMID:Frap-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation. 1116 88

The mechanism and target cell of the life-prolonging effect of interferon-alpha (IFN-alpha) in chronic myelogenous leukemia (CML) are controversial. We studied the influence of IFN-alpha treatment on the frequency of malignant hematopoietic precursor cells in the peripheral blood (PB) of CML patients during the course of the disease. PB 10-day colony-forming cells (PB-CFCs) were assessed with regard to their quantity, lineage distribution, and BCR-ABL status, as determined by fluorescence in situ hybridization (FISH). PB-CFC numbers were determined in 39 patients (29 in the chronic phase, 6 in an advanced stage, and 4 with progression to an advanced stage during follow-up). Thirty-one patients were evaluated either once or several times to determine the BCR-ABL status of the colonies. BCR-ABL negative PB-CFCs were detectable at diagnosis in 5 of 11 patients. A major reduction of BCR-ABL positive colonies to <25% of PB-CFCs was observed in 10/13 determinable IFN-alpha treated patients in early and late chronic phases, indicating a high proportion of BCR-ABL negativity at the clonogenic cell level. In contrast, only 3 of these patients had a cytogenetic response of <25% Philadelphia chromosome (Ph1)-positive metaphases in bone marrow cytogenetics. Treatment with IFN-alpha and/or hydroxyurea (HU) during chronic phase was accompanied by a reduction of PB-CFCs to subnormal levels (median 24 CFCs/ml) compared to controls (median 207 CFCs/ml), untreated patients in chronic phase (median 25,979 CFCs/ml), and patients with advanced disease (median 6,047 CFCs/ml). In blast crisis (6 patients), all colonies tested were BCR-ABL positive. Our results show that IFN-alpha treatment leads to a marked reduction of malignant myeloid precursor cells in the PB of CML patients, which exceeds the degree of cytogenetic remission. This offers an explanation for the good therapeutic efficacy and even life-prolonging effect of IFN-alpha, which is also observed in cytogenetic non-responders.
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PMID:Predominantly BCR-ABL negative myeloid precursors in interferon-alpha treated chronic myelogenous leukemia: a follow-up study of peripheral blood colony-forming cells with fluorescence in situ hybridization. 1123 81


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