Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular or proto-oncogenes are normal cellular genes important in normal cell growth and development. In some instances abnormal expression of these genes is associated with altered cell growth or with malignant transformation. Abnormalities of cellular oncogenes are common in human leukemias. These arise by multiple mechanisms such as mutation, translocation, amplification, and others. Sometimes more than one abnormality is present within a single oncogene. In other instances, a leukemia cell may contain abnormalities of several different oncogenes. Some oncogene abnormalities are relatively specific for certain leukemias and occur in almost all cases; examples include ABL in chronic myelogenous leukemia or MYC in Burkitt leukemia/lymphoma. Other abnormalities are also relatively specific but occur in only some cases such as NRAS in acute myelogenous leukemia or BCL2 in B-cell acute lymphoblastic leukemia. In other leukemias, such as most cases of acute lymphoblastic leukemia and chronic lymphocytic leukemia, oncogene abnormalities are uncommon. The precise role of oncogenes in the pathogenesis of human leukemia is unknown. Retrovirus transduced versions of some of the oncogenes modified in human leukemias cause leukemia in animals. Other oncogenes, modified or unmodified, transform animal and human hematopoietic cells in vitro. Some oncogene products are hematopoietic growth factors or growth factor receptors while others regulate cell proliferation or differentiation by diverse mechanisms. Disruption of the balance between these processes seems the most likely mechanism of oncogene related leukemogenesis. If the role of oncogenes in human leukemias can be defined, innovative diagnostic and therapeutic strategies may be forthcoming.
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PMID:Oncogenes and leukemia. 240 17

Surface markers have been of proven diagnostic and prognostic use in acute lymphoblastic leukemia (ALL). T cell ALL (T-ALL), where blasts possess receptors for sheep red blood cells (R-SRC+), is associated with an adverse prognosis in children and adults. The presence of common ALL antigen (CALLA)-positive blasts (i.e. common-ALL) in children is indicative of a good response to treatment, in contrast to the poor response shown by pre-B-ALL cases, where the blasts are also CALLA-positive but additionally contain cytoplasmic mu chains. Recently a subgroup of T-ALL, immature T-ALL, was identified, where the blasts lack R-SRC and T cell markers (such as T1, T3, T4, T8, T6) but carry a pan T cell antigen (p40) recognized by the monoclonal antibody LAU-A1(12/103 ALL cases in our series). This new subgroup, immature T-ALL (R-SRC-/p40+), also seems to be associated with a poor prognosis, like T-ALL.
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PMID:Contribution of immunological markers to the diagnosis and prognosis of human leukemia. 315 79

Results for adult ALL have improved, with CR rates of 68% to 91% and a cure rate of 25% to 41%. The outcome for patients with T-ALL has especially improved, and the major drugs responsible are C and ara-C. Outcome for B-ALL has improved by using short intensive cycles including, among other drugs, C and high-dose MTX. The inferior outcome of adult ALL compared with childhood ALL seems related to the high proportion of Ph1/BCR-ABL positive ALL patients, which constitute about 30% in adults versus less than 5% in children. The major prognostic factors for survival in adult ALL are age, time to achieve CR, cytogenetic abnormalities, immunologic subtype, and WBC; these may serve as a guide for BMT in first CR. New approaches in the treatment of adult ALL include the use of HGFs, the use of biologic response modifiers, and the detection of MRD to tailor treatment decisions.
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PMID:Therapy of the newly diagnosed adult with acute lymphoblastic leukemia. 844 56

Over a time period of five years leukemic blast samples from 141 consecutive patients with adult ALL were referred to our laboratory, for molecular evaluation of chromosome abnormalities. The t(9;22), t(4;11) and t(1;19) which are most commonly found in adult ALL with a B-precursor phenotype were molecularly analyzed by similar RT-PCR based protocols. BCR-ABL transcripts generated by the t(9;22) translocation were demonstrated in 36 patients (25%) and were restricted to the 109 patients with B precursor ALL (33% of this group). Of 83 patients showing a, common phenotype (CD10+), 34 were BCR-ABL positive (41%) whereas only 2 out of 26 with Null ALL (HLADr+, CD19+, CD10) were positive. Interestingly, the percent of BCR-ABL positive CD1O+ ALL increases significantly with age being 20% in patients less than 30 years old and more than 50% in older patients. None of the T-ALL (24 patients) and B-ALL (8 patients) were positive. The majority of cases (67%) showed the p190 gene subtype. The cytogenetic diagnosis of Philadelphia chromosome was always confirmed by the molecular analysis and this approach allowed for the detection of the presence of the BCR-ABL rearrangement in 26 patients when a negative result or no metaphases were obtained. The complete remission rate was similar among BCR-ABL positive and negative patients but a shorter remission duration was observed in those showing molecular evidence of t(9;22) and this finding was significantly evident in CD1O+ ALL patients. By means of comparison, in most of the same adult ALL patients, we analyzed the yet unrecognized prevalence of the t(4;11) and t(1;19) translocations by the molecular analysis of their chromosomal breakpoints. Rearrangements of the ALL-1 gene on 11q23 band and ALL- l1AF.4 fusion transcripts specific for the t(4;11) were demonstrated in 7 out of the 21 Null ALL investigated, with no additional positive cases found among the other ALL subgroups. Overall the clinical behavior of t(4; 11) positive patients was dismal with a very short CR duration. Chimeric E2A-PBX1 transcripts generated by the t(1;19) were found in only two of the 87 B-precursor ALL analyzed. The presented results provide further evidence for the utility of RT-PCR based methods for the molecular diagnosis of chromosome translocations in ALL. The identification of such abnormalities can significantly contribute to the identification of more appropriate therapeutic options for standard and high risk ALL patients
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PMID:Molecular diagnosis and clinical relevance of t(9;22), t(4;11) and t(1 ;19) chromosome abnormalities in a consecutive group of 141 adult patients with acute lymphoblastic leukemia. 917 11

BCR-ABL(p190) oncogene is the result of a reciprocal translocation between chromosomes 9 and 22 and is associated with B-cell acute lymphoblastic leukemia (B-ALL) in humans. Current models expressing the BCR-ABL(p190) chimeric gene fail to consistently reproduce the phenotype with which the fusion gene is associated in human pathology, mainly due to the difficulty of being expressed in the appropriate cell type in vivo. We have used here homologous recombination in ES cells to create an in-frame fusion of BCR-ABL(p190) that mimics the consequences of the human chromosomal translocation by fusion of BCR-ABL coding sequences into the bcr endogenous gene. The chimeric mice generated with the mutant embryonic stem cells systematically develop B-ALL. Using these chimeric mice, we further show that BCR-ABL oncogene does not require the endogenous bcr product in leukemogenesis. Our results show that BCR-ABL(p190) chimeric mice are a new model to study the biology of the BCR-ABL oncogene and indicate the efficacy of this strategy for studying the role of specific chromosome abnormalities in tumor development.
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PMID:A BCR-ABL(p190) fusion gene made by homologous recombination causes B-cell acute lymphoblastic leukemias in chimeric mice with independence of the endogenous bcr product. 931 Apr 67

Bruton's tyrosine kinase (BTK) is a member of the Src-related Tec family of protein tyrosine kinases. Mutations in the btk gene have been linked to severe developmental blocks in human B-cell ontogeny leading to X-linked agammaglobulinemia. Here, we provide unique biochemical and genetic evidence that BTK is an inhibitor of the Fas/APO-1 death-inducing signaling complex in B-lineage lymphoid cells. The Src homology 2, pleckstrin homology (PH), and kinase domains of BTK are all individually important and apparently indispensable, but not sufficient, for its function as a negative regulator of Fas-mediated apoptosis. BTK associates with Fas via its kinase and PH domains and prevents the FAS-FADD interaction, which is essential for the recruitment and activation of FLICE by Fas during the apoptotic signal. Fas-resistant DT-40 lymphoma B-cells rendered BTK-deficient through targeted disruption of the btk gene by homologous recombination knockout underwent apoptosis after Fas ligation, but wild-type DT-40 cells or BTK-deficient DT-40 cells reconstituted with wild-type human btk gene did not. Introduction of an Src homology 2 domain, a PH domain, or a kinase domain mutant human btk gene into BTK-deficient cells did not restore the resistance to Fas-mediated apoptosis. Introduction of wild-type BTK protein by electroporation rendered BTK-deficient DT-40 cells resistant to the apoptotic effects of Fas ligation. BTK-deficient RAMOS-1 human Burkitt's leukemia cells underwent apoptosis after Fas ligation, whereas BTK-positive NALM-6-UM1 human B-cell precursor leukemia cells expressing similar levels of Fas did not. Treatment of the anti-Fas-resistant NALM-6-UM1 cells with the leflunomide metabolite analog alpha-cyano-beta-methyl-beta-hydroxy-N-(2, 5-dibromophenyl)propenamide, a potent inhibitor of BTK, abrogated the BTK-Fas association without affecting the expression levels of BTK or Fas and rendered them sensitive to Fas-mediated apoptosis. The ability of BTK to inhibit the pro-apoptotic effects of Fas ligation prompts the hypothesis that apoptosis of developing B-cell precursors during normal B-cell ontogeny may be reciprocally regulated by Fas and BTK.
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PMID:Bruton's tyrosine kinase as an inhibitor of the Fas/CD95 death-inducing signaling complex. 988 May 44

The pattern of expression of the human Emt tyrosine kinase was established in healthy individuals and hematological malignancies by RT-PCR from bone marrow and blood samples, fractionated into T-cells, B-cells, monocytes, granulocytes and thrombocytes. Previously studied mostly in murine samples or established human cell lines, the in vivo correlation was here further clarified. In hematopoietic cells, expression of the EMT gene was associated with T-cell fractions, but Emt was not detected in cord blood CD34+ cells. In fetal tissues, Emt mRNA was strongly expressed in thymus, no expression could be detected in non-hematopoietic tissues. The expression pattern of the 48 malignant bone marrow samples (23 ALL, 1 PLL, 9 AML, 7 CLL and 8 CML cases) paralleled the findings from normal hematopoietic cells: 9/11 T cell associated ALLs, as well as one T-PLL sample, but only 1/12 samples of B-ALL expressed Emt markedly. Only minor signs of Emt expression could be shown in the AML samples, while CML and CLL samples were totally devoid of expression. In addition the Emt protein could be detected by Western blotting from T-lymphocytes and T-cell associated ALL, corresponding to mRNA expression. In conclusion, Emt (Itk) is T-cell associated both in normal and leukemic cells, but is not expressed in cord blood CD34+ cells, suggesting that Emt expression is switched on only later in T-cell development. In addition, an association between Emt and CD2 expression remains even in malignancies.
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PMID:Human Emt tyrosine kinase is specifically expressed both in mature T-lymphocytes and T-cell associated hematopoietic malignancies. 1004 24

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.
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PMID:Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells. 1087 99

The optimization of conventional treatment approaches, such as chemotherapy, stem cell transplantation (SCT), and supportive care, and the exploration of new approaches will hopefully further improve the outcome of adults with acute lymphoblastic leukemia (ALL). Subgroup-adjusted treatment has already greatly improved treatment outcomes in T- and mature B-cell ALL. These approaches should be further refined, for example, in T-ALL with cyclophosphamide and cytarabine, in pro-B ALL with high-dose cytarabine (HdAC), in B-precursor ALL with high-dose methotrexate (HdM) and 6-mercaptopurine (6-MP), and in mature B-ALL with HdM and HdAC. The indications for SCT will be extended to include elderly patients undergoing allogeneic mini-transplants, and tumor eradication will be improved by better conditioning regimens such as radioimmunoconjugates and methods to induce the graft-versus-leukemia (GvL) effect, such as donor leukocyte infusions (DLI) or allogeneic mini-transplants applied after autologous transplants. Molecular therapeutic approaches, for example, those directed against the fusion protein BCR-ABL with ABL-tyrosine kinase inhibitor, are on the way to creating a new avenue for the treatment of ALL. In the future, drug resistance should be exploited as a pretherapeutic test for treatment strategies, but whether multidrug resistance modulation with available drugs will be used in ALL remains open. Evaluation of the pharmacokinetics of cytostatic drugs and the pharmacogenomics of cytostatic agents in adult ALL may contribute to the development of individualized treatment strategies with higher efficacy and lower toxicity. Minimal residual disease (MRD) evaluation is attractive in adult ALL, because it can be determined in a very high percentage of patients. It has been shown to be predictive for relapse and might be of benefit for redefinition of complete remission (CR), for determination of the efficacy of single treatment elements, and for treatment tailoring during the course of disease. New treatment approaches include also several forms of immunotherapy for B- as well as T-lineage ALL; after the demonstration that such approaches are also effective in ALL, their optimal place in the treatment strategy for adult ALL can be determined.
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PMID:New approaches to acute lymphoblastic leukemia in adults: where do we go? 1104 22

The Philadelphia chromosome (Ph+) reflects a balanced reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11.2] involving the BCR and ABL genes. At present, detection of BCR/ABL gene rearrangements is mandatory in precursor-B-ALL patients at diagnosis for prognostic stratification and treatment decision. In spite of the clinical impact, no screening method, displaying a high sensitive and specificity, is available for the identification of BCR/ABL+ precursor-B-ALL cases. The aim of the present study was to explore the immunophenotypic characteristics of precursor B-ALL cases displaying BCR/ABL gene rearrangements using multiple stainings analyzed by quantitative flow cytometry in order to rapidly (<1 h) identify unique phenotypes associated with this translocation. From the 82 precursor-B-ALL cases included in the study 12 displayed BCR/ABL gene rearragements, all corresponding to adult patients, four of which also displayed DNA aneuploidy. Our results show that BCR/ABL+ precursor B-ALL cases constantly displayed a homogeneous expression of CD10 and CD34 but low and relatively heterogeneous CD38 expression, together with an aberrant reactivity for CD13. In contrast, this unique phenotype was only detected in three out of 70 BCR/ABL cases. Therefore, the combined use of staining patterns for CD34, CD38 and CD13 expression within CD10-positive blast cells is highly suggestive of BCR/ABL gene rearrangements in adults with precursor B-ALL.
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PMID:Adult precursor B-ALL with BCR/ABL gene rearrangements displays a unique immunophenotype based on the pattern of CD10, CD34, CD13 and CD38 expresssion. 1158 32


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