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 mechanisms by which interferon-alpha (IFN-alpha) mediates its anti-leukemic effects in chronic myelogenous leukemia (CML) cells are not known. We determined whether p38 MAPK is activated by IFN-alpha in BCR-ABL-expressing cells and whether its function is required for the generation of growth inhibitory responses. IFN-alpha treatment induced phosphorylation/activation of p38 in the IFN-alpha-sensitive KT-1 cell line, but not in IFN-alpha-resistant K562 cells. Consistent with this, IFN-alpha treatment of KT-1 (but not K562) cells induced activation of the small GTPase Rac1, which functions as an upstream regulator of p38. In addition, IFN-alpha-dependent phosphorylation/activation of p38 was induced by treatment of primary granulocytes isolated from the peripheral blood of patients with CML. To define the functional role of the Rac1/p38 MAPK pathway in IFN-alpha signaling, the effects of pharmacological inhibition of p38 on the induction of IFN-alpha responses were determined. Treatment of KT-1 cells with the p38-specific inhibitors SB203580 and SB202190 reversed the growth inhibitory effects of IFN-alpha. On the other hand, the MEK kinase inhibitor PD098059 had no effects, further demonstrating the specificity of these findings. To directly determine the significance of IFN-alpha-dependent activation of p38 in the induction of the anti-leukemic effects of IFN-alpha, we evaluated the effects of p38 inhibition on leukemic colony formation in bone marrow samples of patients with CML. IFN-alpha inhibited leukemic granulocyte/macrophage colony formation in a dose-dependent manner, whereas concomitant treatment with p38 inhibitors reversed such an inhibition. Thus, the Rac1/p38 MAPK pathway is activated by IFN-alpha in BCR-ABL-expressing cells and appears to play a key role in the generation of the growth inhibitory effects of IFN-alpha in CML cells.
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PMID:The p38 MAPK pathway mediates the growth inhibitory effects of interferon-alpha in BCR-ABL-expressing cells. 1135 67

Chronic hepatitis B infection is frequently diagnosed within the genitourinary clinic setting with sexual transmission the commonest route of acquisition in the United Kingdom. Only 3--5% of adults who contract acute hepatitis B will progress to chronic infection, and these individuals can be identified by the presence of hepatitis B surface antigen (HBsAg) in the bloodstream 6 months after infection. Individuals at highest risk of long-term complications such as cirrhosis and hepatocellular carcinoma, carry HBeAg and have high levels of circulating hepatitis B virus (HBV) deoxyribonucleic acid (DNA). Therapy should be targeted towards this group of patients. Two forms of therapy are now licensed for use in chronic hepatitis B infection: interferon-alpha and lamivudine. Seroconversion occurs in 30--40% of patients treated with interferon and treatment is often limited by toxicity. Lamivudine is well tolerated with seroconversion rates of 15--20% at one year, rising with increasing duration of therapy. Long-term monotherapy is limited however by the development of resistance mutations and combination nucleoside therapy is likely to become the treatment of choice in the future. Patients with chronic hepatitis B should be counselled regarding transmission, partner vaccination and alcohol intake and co-infection with other hepatitis viruses should be excluded.
Int J STD AIDS 2001 Jun
PMID:The management of chronic hepatitis B infection. 1180 40

For the management of chronic myeloid leukemia (CML), prediction or early determination of the response to interferon-alpha (IFN-alpha) treatment is important for identifying nonresponder patients to whom alternative therapy may be proposed. In this study, the levels of expression of both BCR-ABL and subunit 2c of IFN-alpha receptor (IFN-alphaR2c) genes were analyzed at diagnosis in 74 patients with chronic phase CML treated with an IFN-alpha monotherapy. By using blood samples, real-time quantitative polymerase chain reaction was performed to quantify BCR-ABL, IFN-alphaR2c, and G6PDH mRNA as external control. The results were compared with hematologic and cytogenetic responses to IFN-alpha. A wide variation in the BCR-ABL/G6PDH ratio was observed at diagnosis (median, 6.68%; range, 0.18%-41.31%), but no significant association with response to IFN-alpha was observed. In contrast, the variation of IFN-alphaR2c/G6PDH ratio at diagnosis was significantly associated with the achievement of major cytogenetic response (MCR; 34% or lower Ph(+) metaphases). Median values of IFN-alphaR2c/G6PDH ratio for patients achieving MCR and for those who did not achieve it were 110.75% (range, 9.47%-612.30%) and 64.42% (range, 5.96%-425.40%), respectively (P =.037). In addition, this novel molecular factor, combined with the achievement of complete hematologic response at 3 months, makes it possible to predict MCR achievement with high probability by Kaplan-Meier analysis (91% +/- 17% at 24 months; P =.0001). (Blood. 2001;97:3568-3573)
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PMID:Expression of interferon-alpha (IFN-alpha) receptor 2c at diagnosis is associated with cytogenetic response in IFN-alpha-treated chronic myeloid leukemia. 1136 52

Chronic myeloid leukaemia (CML) is characterized by marked expansion of the myeloid series, and is thought to arise as a direct result of the bcr-abl fusion-gene. The BCR-ABL oncoprotein is a constitutively active protein tyrosine kinase (PTK), which results in altered cell signalling and is responsible for the changes that characterize the malignant cells of CML. It has been shown that the increased tyrosine kinase activity of BCR-ABL is a requirement for transformation and is, therefore, a legitimate target for pharmacological inhibition. Several compounds have now been identified as relatively selective inhibitors of BCR-ABL, including members of the tyrphostin family, herbimycin A and most importantly the 2-phenylaminopyrimidine ST1571. Having established the efficacy of this agent in vitro, phase I trials using an oral formulation were commenced in the USA in mid 1998. Early data from an interferon-alpha (IFN) resistant/refractory or intolerant cohort demonstrated good patient tolerance and effective haematological control at doses above 300 mg. More promising was its ability to induce cytogenetic responses in this pretreated group of patients. Phase II data, albeit far from complete, appear to confirm its efficacy even in the context of advanced disease and phase III clinical trials are currently underway in many countries. Recent laboratory evidence, however, suggests that the development of drug resistance is a possibility (via amplification of the bcr-abl fusion gene, overexpression of P-glycoprotein or binding of ST1571 to alpha1 acid glycoprotein) and that combination therapy including ST1571 should be considered.
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PMID:Tyrosine kinase inhibitors in the treatment of chronic myeloid leukaemia: so far so good? 1140 8

Janus kinase 1 (Jak1) is a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors. Here we show that the in vitro translated N-terminal domains of Jak1 are sufficient for binding to a biotinylated peptide comprising the membrane-proximal 73 amino acids of gp130, the signal-transducing receptor chain of interleukin-6-type cytokines. By the fold recognition approach amino acid residues 36-112 of Jak1 were predicted to adopt a beta-grasp fold, and a structural model was built using ubiquitin as a template. Substitution of Tyr(107) to alanine, a residue conserved among Jaks and involved in hydrophobic core interactions of the proposed beta-grasp domain, abrogated binding of full-length Jak1 to gp130 in COS-7 transfectants. By further mutagenesis we identified the loop 4 region of the Jak1 beta-grasp domain as essential for gp130 association and gp130-mediated signal transduction. In Jak1-deficient U4C cells reconstituted with the loop 4 Jak1 mutants L80A/Y81A and Delta(Tyr(81)-Ser(84)), the interferon-gamma, interferon-alpha, and interleukin-6 responses were similarly impaired. Thus, loop 4 of the beta-grasp domain plays a role in the association of Jak1 with both class I and II cytokine receptors. Taken together the structural model and the mutagenesis data provide further insight into the interaction of Janus kinases with cytokine receptors.
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PMID:Mapping of a region within the N terminus of Jak1 involved in cytokine receptor interaction. 1146 94

STI571, a BCA-ABL tyrosine kinase inhibitor, has appeared in molecular targeted therapy as a new treatment option for patients with chronic myelogenous leukemia (CML) through rational drug development. In a phase I study in the USA, adverse effects were minimal. Complete hematologic response was observed in 98% of patients with chronic phase CML treated with a daily dose of 300 mg or more, and cytogenetic response was seen in 31% of patients. STI571 has substantial activity in the blast crisis of CML and Ph + ALL. Stem cell transplantation (SCT) may be compared with interferon-alpha (IFN-alpha) therapy from three analyses reported according to risk assessment. These studies indicated that SCT increased survival only in patients who were younger and at intermediate or high risk; however, survival with SCT in older patients at higher risk was no better than with IFN-alpha therapy in a Japanese prospective study. An individualized risk assessment-based approach is useful in prioritizing SCT and IFN-alpha in patients with chronic phase CML.
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PMID:[Chronic myelogenous leukemia]. 1157 30

Persistence of BCR-ABL rearrangements was demonstrated by D-FISH technique in chronic myeloid leukemia (CML) patients in complete cytogenetic response (CCR) after allogeneic bone marrow transplantation (BMT) or interferon-alpha therapy (IFN-alpha). Samples from bone marrow aspirate or peripheral blood or both were analyzed by conventional cytogenetics, Southern blot, fluorescent interphase 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 were negative or weakly positive. Based on these results, we hypothesize that the BCR-ABL genomic rearrangement remains unexpressed in a small percentage of cells whatever the treatment (IFN-alpha or BMT), and this in spite of the negativity of the RT-PCR-based classical molecular remission criterion. These data corroborate those obtained by other investigators and point to the need for follow-up of CML patients in CCR over an extensive period, at the DNA level to evaluate the residual disease and at the RNA level (Q-RT-PCR) to estimate the risk of relapse and guide the therapeutic decision. Experimental models suggesting the persistence of positive BCR-ABL cells are discussed and tentative explanations of tumor "dormancy" are proposed.
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PMID:Persistence of transcriptionally silent BCR-ABL rearrangements in chronic myeloid leukemia patients in sustained complete cytogenetic remission. 1169 48

The accuracy of cytogenetic diagnosis in the management of hematological malignancies has improved significantly over the past 10 years. Fluorescence in situ hybridization (FISH), a technique of molecular cytogenetics, has played a pivotal role in the detection of unique sub-microscopic chromosomal rearrangements that helped in the identification of chromosomal loci, which contain genes involved in leukemogenesis. We studied the feasibility and sensitivity of the FISH technique for molecular analysis of translocations markers, t(9;22) and t(15;17) for accurate molecular diagnosis and for monitoring the disease in 21 patients with chronic myeloid leukemia (CML) who received interferon-alpha and/or chemotherapy (7 patients), bone marrow transplantation (14 patients), and 14 patients with acute promyelocytic leukemia (APL) who received all-trans-retinoic acid (ATRA) and/or chemotherapy. We also applied conventional karyotyping (CK) for identification of t(9;22) and t(15;17) at diagnosis. All CML cases had a Ph; t(9;22) and except for two cases all APL had t(15;17). The FISH studies on CML marrows in complete cytogenetic remission (CCR) (100% Ph- by CK) achieved by IFN-alpha, showed 0-2.5% of cells with BCR-ABL fusion in first cytogenetic remission (Controls, range 0.5-1.5%). Repeat follow-up FISH studies could be done in two cases in remission, which demonstrated 0-10% of cells with BCR-ABL fusion. Evaluation of Ph positive status of CML marrow at diagnosis by CK (100% Ph+ cells) and FISH (80-92% BCR-ABL fusion) pointed the existence of dormant clone of normal residual hematopoietic cells along with actively proliferating clones of Ph positive cells. Fluorescence in situ hybridization analysis of post-BMT CML marrows in CCR (0% Ph+ mitoses) could detect MRD with range of 1-6%. Among 14 patients, 9 who showed percentage of BCR-ABL positive cells (0.0-1.5%) almost similar to normal controls, 6 patients had comparatively good prognosis (disease-free survival 7-14 months). Of five patients with residual leukemic cells in the range of 2-6%, 4 relapsed within a period of 3-24 months. Fourteen APL patients in CCR [100% t(15;17) negative cells by CK] were evaluated by FISH to check the presence of residual leukemic cells. In these patients FISH could efficiently detect 1-14.5% of residual cells with PML-RARA (patients mean MRD 5%, controls mean MRD 3.5%, P=.02). Since the time of FISH analysis, 5 to 7 patients with higher fraction of leukemic cells (5-11%) relapsed within a short period (1-7 months). On the contrary, 5 of 7 patients with either absence or low percentage of PML-RARA positive cells remained in complete remission for 11-24 months. Our data show that FISH has a potential to detect and measure the fraction of aberrant malignant cells in remission marrows, induced by BMT in CML and chemotherapy in APL. These findings encourage the investigations on a large scale to merit its potential for identification of patients at high risk. In the present studies, FISH on interphase cells also demonstrated its efficiency in the molecular diagnosis by its ability to detect BCR-ABL and PML-RARA fusion in CML with masked/variant Ph and t(15;17) negative APL, respectively. The efficiency of technique in molecular diagnosis was also proved in one of the CML patients who progressed to myeloid blastic phase where interphase FISH could identify an extra BCR-ABL fusion on both chromosomes 9 indicating insertion of BCR into ABL and its duplication.
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PMID:Fluorescence in situ hybridization: a highly efficient technique of molecular diagnosis and predication for disease course in patients with myeloid leukemias. 1175 52

For patients with chronic myeloid leukaemia, methods for monitoring response to treatment have changed considerably in recent years. In the 1980s, the principal approach was repeated examination of bone marrow metaphases for the presence of the Ph chromosome in patients treated by interferon-alpha (IFN-alpha) or allogeneic stem cell transplantation. The use of fluorescence in situ hybridisation (FISH) techniques to detect the BCR-ABL fusion gene in Ph-positive leukaemia cells increased the sensitivity of cytogenetic studies to some degree. In the last 10 years, the reverse-transcriptase polymerase chain reaction (RT-PCR) has proved extremely valuable for assessing and monitoring minimal residual disease in patients who achieve Ph negativity after treatment with IFN-alpha or with the new Abl tyrosine kinase inhibitor imatinib mesylate or after allogeneic stem cell transplantation (SCT). Results are consistent with the notion that the majority of long-term survivors after allogeneic SCT are probably 'cured'; for other patients monitored serially in complete cytogenetic remission, rising numbers of BCR-ABL transcripts detected by RT-PCR can indicate the need for further therapy.
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PMID:Cytogenetic and molecular monitoring of residual disease in chronic myeloid leukaemia. 1191 87

In many ways, chronic myeloid leukaemia (CML) serves as a paradigm for the utility of molecular methods in the diagnosis of malignancy or for monitoring the response of the patient to therapy. The Philadelphia (Ph) translocation provides an elegant example of how cytogenetic findings provided the starting point for understanding the genetic mechanisms involved in leukaemogenesis. The degree of reduction in tumour load after therapy is an important prognostic factor for CML patients. Several approaches have been introduced that can specifically detect the Ph translocation or its products; these approaches include fluorescent in situ hybridization, Southern blotting, western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). Because non-quantitative RT-PCR analysis after therapy gives only limited information, quantitative or semiquantitative RT-PCR assays have been developed that enable the kinetics of residual BCR-ABL transcripts to be monitored over time in patients after allogeneic stem cell transplantation, interferon-alpha, or STI571 therapy.
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PMID:Minimal residual disease in chronic myeloid leukaemia patients. 1198 22


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