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)

B-cell receptor signaling contributes to apoptosis resistance in chronic lymphocytic leukemia (CLL), limiting the efficacy of current therapeutic approaches. In this study, we investigated the expression of spleen tyrosine kinase (SYK), a key component of the B-cell receptor signaling pathway, in CLL and its role in apoptosis. Gene expression profiling identified enhanced expression of SYK and downstream pathways in CLL compared with healthy B cells. Immunoblotting showed increased expression and phosphorylation of SYK, PLCgamma(2), signal transducers and activators of transcription 3, and extracellular signal regulated kinase 1/2 in CLL compared with healthy B cells, suggesting enhanced activation of these mediators in CLL. SYK inhibitors reduced phosphorylation of SYK downstream targets and induced apoptosis in primary CLL cells. With respect to prognostic factors, SYK inhibitors exerted stronger cytotoxic effects in unmutated and ZAP70(+) cases. Cytotoxic effects of SYK inhibitors also associated with SYK protein expression, potentially predicting response to therapy. Combination of fludarabine with SYK Inhibitor II or R406 increased cytotoxicity compared with fludarabine therapy alone. We observed no stroma-contact-mediated drug resistance for SYK inhibitors as described for fludarabine treatment. CD40 ligation further enhanced efficacy of SYK inhibition. Our data provide mechanistic insight into the recently observed therapeutic effects of the SYK inhibitor R406 in CLL. Combination of SYK inhibitors with fludarabine might be a novel treatment option particularly for CLL patients with poor prognosis and should be further evaluated in clinical trials.
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PMID:Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. 1954 11

JAK2 mutation has not been described in patients with chronic lymphocytic leukemia (CLL). We found JAK2 mutation in a patient with CLL and coexisting myeloproliferative neoplasm (MPN). In this patient, we demonstrated the presence of the JAK2 mutation in CD34(+) progenitor cells, myeloid lineage cells, megakaryocytes, B lymphocytes but not in T lymphocytes. This case represents the first case report of JAK2 mutation in CLL and may also suggest that, JAK2 mutation most likely represents a secondary event from primary gene mutations involving the primitive stem cells which give rise to MPN and CLL. Furthermore, in this case, we believe that we are the first to demonstrate that JAK2 mutation in myeloid and B lymphoid cells but not T lymphocytes in a case of coexisting CLL and MPN.
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PMID:JAK2 mutation in a patient with CLL with coexistent myeloproliferative neoplasm (MPN). 1962 83

Fc receptor-like 2 (FCRL2) is highly expressed on B-cell chronic lymphocytic leukemia (B-CLL) cells and could possibly influence disease pathogenesis. Therefore, we investigated FCRL2 mRNA expression in a large cohort with 152 CLL patients in order to assess its role in risk prediction in B-CLL. FCRL2 mRNA expression was found to be expressed at considerably higher levels in peripheral blood mononuclear cells (PBMC) of B-CLL patients compared to controls (range 1.35- to 210-fold upregulation; P < 0.0001) and cells of other hematological diseases. Patients with high FCRL2 expression (according to ROC-analysis) had a significantly longer treatment-free survival (TFS) and overall survival (OS) than patients with low FCRL2 expression (median TFS: 119 vs. 34 months, P < 0.0001; median OS: 321 months vs. not reached, P = 0.009). Univariate comparisons found that FCRL2 expression was weakly associated with IGHV mutation status (P = 0.05), CD38 status (P < 0.0001) and ZAP-70 status (P < 0.0001). Furthermore, we show that the combination of FCRL2 with ZAP70-, CD38- or IGHV-status could further significantly refine the prognostic information provided by either of the factors alone in TFS and OS. In multivariate analysis low FCRL2 expression was a significant independent prognostic factor (HR 2.4; P = 0.005). Here we demonstrate that the level of FCRL2 expression is correlated with prognosis in B-CLL.
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PMID:FCRL2 mRNA expression is inversely associated with clinical progression in chronic lymphocytic leukemia. 1968 11

Although activation of the B-cell receptor (BCR) signaling pathway is implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), its clinical impact and the molecular correlates of such response are not clearly defined. T-cell leukemia 1 (TCL1), the AKT modulator and proto-oncogene, is differentially expressed in CLL and linked to its pathogenesis based on CD5(+) B-cell expansions arising in TCL1-transgenic mice. We studied here the association of TCL1 levels and its intracellular dynamics with the in vitro responses to BCR stimulation in 70 CLL cases. The growth kinetics after BCR engagement correlated strongly with the degree and timing of induced AKT phospho-activation. This signaling intensity was best predicted by TCL1 levels and the kinetics of TCL1-AKT corecruitment to BCR membrane activation complexes, which further included the kinases LYN, SYK, ZAP70, and PKC. High TCL1 levels were also strongly associated with aggressive disease features, such as advanced clinical stage, higher white blood cell counts, and shorter lymphocyte doubling time. Higher TCL1 levels independently predicted an inferior clinical outcome (ie, shorter progression-free survival, P < .001), regardless of therapy regimen, especially for ZAP70(+) tumors. We propose TCL1 as a marker of the BCR-responsive CLL subset identifying poor prognostic cases where targeting BCR-associated kinases may be therapeutically useful.
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PMID:High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia. 1977 Mar 58

Although chromosome 17p abnormalities and TP53 mutations have been reported as poor prognostic indicators in chronic lymphocytic leukemia (CLL), the impact of aberrant p53 expression as assessed by immunohistochemistry (p53-IHC) has not been defined in patients with CLL treated with chemoimmunotherapy, particularly in the context of other novel markers such as ZAP-70 expression and IgVH mutation status (IgVH MS). We assessed p53-IHC in 222 bone marrow (BM) specimens from patients with CLL enrolled in a phase II trial with fludarabine, cyclophosphamide, and rituximab (FCR). ZAP70 expression and IgVH MS were assessed in 208 and 108 patients, respectively. One hundred sixty-eight patients had concurrent classical cytogenetic analysis. p53-IHC correlated with abnormal karyotype (p = 0.002) and adversely affected overall survival independent of ZAP70 expression and IgVH MS (p < 0.001). Patients with p53-IHC(+) CLL were less likely to achieve complete remission, but patients who did achieve complete remission showed a durable response. In this patient cohort, p53-IHC is an important determinant of complete remission and overall survival, but not remission duration, in patients with CLL receiving FCR.
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PMID:p53 expression by immunohistochemistry is an important determinant of survival in patients with chronic lymphocytic leukemia receiving frontline chemo-immunotherapy. 1970 50

CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients.
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PMID:Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death. 1992 52

Copy number losses in chromosome arm 9p are well-known aberrations in malignancies, including leukemias. The CDKN2A gene is suggested to play a key role in these aberrations. In this study overviewing 9p losses in hematologic neoplasias, we introduce the term focal 9p instability to indicate multiple areas of copy number loss or homozygous loss within a larger heterozygous one in 9p. We have used microarray comparative genomic hybridization to study patients with acute lymphoblastic leukemia (ALL, n = 140), acute myeloid leukemia (n = 50), chronic lymphocytic leukemia (n = 20), and myelodysplastic syndromes (n = 37). Our results show that 9p instability is restricted to ALL. In total, 58/140 (41%) patients with ALL had a loss in 9p. The 9p instability was detected in 19% of the patients with ALL and always included homozygous loss of CDKN2A along with loss of CDKN2B. Other possibly important genes included MTAP, IFN, MLLT3, JAK2, PTPLAD2, and PAX5. 13/27 (48%) patients with the instability had the BCR/ABL1 fusion gene or other oncogene-activating translocation or structural aberrations. Two patients had homozygous loss of hsa-mir -31, a microRNA known to regulate IKZF1. IKZF1 deletion at 7p12.1 was seen in 10 (37%) patients with the 9p instability. These findings suggest that, in ALL leukemogenesis, loss of CDKN2A and other target genes in the instability region is frequently associated with BCR/ABL1 and IKZF1 dysfunction. The multiple mechanisms leading to 9p instability including physical or epigenetic loss of the target genes, loss of the microRNA cluster, and the role of FRA9G fragile site are discussed.
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PMID:Focal 9p instability in hematologic neoplasias revealed by comparative genomic hybridization and single-nucleotide polymorphism microarray analyses. 2001 97

This study was aimed to detect the telomere length and the telomerase expression activity in patients with chronic lymphocytic leukemia (CLL), and investigate their relation to prognosis of CLL. The telomere length and the telomerase expression activity of peripheral blood and / or bone marrow mononuclear cells were examined by Tel-FISH, a semi-quantitative method and by TRAP-ELISA respectively; the expressions of ZAP70 and CD38 were detected by flow cytometry. The results showed that comparing the telomere length in different stages, there was a tendency that the telomere became prolonged when the stage raised up. There was statistical significant difference between Rai stages III-IV and stage 0, Rai stages III-IV and stages I-II, Binet stage C and stage A, Binet stage C and stage B; while no statistical significant difference existed between Rai stage 0 and stages I-II, Binet stage A and stage B. The telomere length in ZAP70 negative group was found similar as in ZAP70 positive group. The telomere length in CD38 positive group was shorter than that in CD38 negative group, but there was no statistical difference between them. Comparing the telomerase expression activity between different stages, there was a tendency that it increased when the stages went up; comparing the telomerase expression activity at different Rai stages, it increased at the higher stages. One case of CLL demonstrated that telomerase expression did not show at remission stage, but was found at relapse stage, which suggested that telomerase expression may relate to prognosis of disease. It is concluded that the telomerase length is in relation to Rai and Binet stage, which was shorter at higher stage than that at lower stage and intermediate stage. It seemed that the telomerase expression activity increased at higher stages. The expression of telomerase in mononuclear cells is stable and not influenced by treatment.
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PMID:[Telomere length and telomerase expression activity in mononuclear cells of patients with chronic lymphocytic leukemia]. 2003 Sep 16

The recent and rapid development of molecularly targeted therapy is best illustrated by advances in the management of haematological malignancy. In myeloid diseases we have seen dramatic improvements in the overall survival and quality of life for patients with chronic myeloid leukaemia treated with ABL and Src/ABL kinase inhibitors and we are poised to discover whether JAK2 inhibitors may offer similar benefit in myeloproliferative diseases. For acute myeloid leukaemia, the introduction of ATRA and myelotarg have had major impacts on the design of therapy regimens and many novel targeted agents, including farnesyl transferase, FLT3 and histone deacetylase inhibitors, are now in clinical trial. In lymphoid malignancies the highlight has been the introduction of rituximab, with significant improvements in the management of non-Hodgkin lymphoma and chronic lymphocytic leukaemia. The last 10 years has experienced a rapidly expanding interest and acceptance that leukaemic stem cells, including an improved ability to target them, may hold the key to improved response and reduced relapse rates across both myeloid and lymphoid disease. We now eagerly anticipate an era in which a wealth of preclinical discoveries are progressed to the clinic.
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PMID:Targeted therapy in haematological malignancies. 2004 51

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease exhibiting variable clinical course and survival rates. Mutational status of the immunoglobulin heavy chain variable regions (IGHVs) of CLL cells offers useful prognostic information for high-risk patients, but time and economical costs originally prevented it from being routinely used in a clinical setting. Instead, alternative markers of IGHV status, such as zeta-associated protein (ZAP70) or messenger RNA levels are often used. We report a (1)H-NMR-based metabolomics approach to examine serum metabolic profiles of early stage, untreated CLL patients (Binet stage A) classified on the basis of IGHV mutational status or ZAP70. Metabolic profiles of CLL patients (n=29) exhibited higher concentrations of pyruvate and glutamate and decreased concentrations of isoleucine compared with controls (n=9). Differences in metabolic profiles between unmutated (UM-IGHV; n=10) and mutated IGHV (M-IGHV; n=19) patients were determined using partial least square discriminatory analysis (PLS-DA; R(2)=0.74, Q(2)=0.36). The UM-IGHV patients had elevated levels of cholesterol, lactate, uridine and fumarate, and decreased levels of pyridoxine, glycerol, 3-hydroxybutyrate and methionine concentrations. The PLS-DA models derived from ZAP70 classifications showed comparatively poor goodness-of-fit values, suggesting that IGHV mutational status correlates better with disease-related metabolic profiles. Our results highlight the usefulness of (1)H-NMR-based metabolomics as a potential non-invasive prognostic tool for identifying CLL disease-state biomarkers.
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PMID:Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups. 2009 Jul 81


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