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)

Ph1-positive leukemias consist of acute leukemia (Ph1 AL) and CML. Cytogenetically, Ph1 AL is often associated with +6, -7, +8, +21, or +Ph1. CML is predominantly accompanied by +Ph1, +8, i (17q), +19 in myeloid crisis and +Ph1, +8, +21 in lymphoid crisis. Thus, i(17q) seems specific for myeloid crisis of CML. Ph1 constricts ABL/BCR within M-BCR in CML and in one half of the adult Ph1 AL. BCR breaks upstream to M-BCR in the other half of adult AL and in most of childhood AL. However, the breakpoint does not affect clinical and hematological features in AL. Consequently, there seems to be two types of Ph1 leukemia; one is AL representing m-BCR rearrangement and the other is CML and Ph1 AL showing M-BCR rearrangement.
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PMID:[Ph1-positive leukemia: cytogenetic outline and prognosis]. 151 45

The Philadelphia chromosome defines chronic myeloid leukemia, and is mostly based on a translocation t(9;22) with a typical BCR-ABL rearrangement which also occurs in so called atypical translocations. The transformation of chronic myeloid leukemia is associated with clonal evolution in 80% of cases. The appearance of an isochromosome 17q unequivocally heralds the onset of a myeloid type of blast crisis. Treatment of Ph-positive CML has still to be considered palliative except for allogeneic bone marrow transplantation. The Philadelphia chromosome is also found in about 20% of patients with acute lymphoblastic leukemia and in about 2% of patients with nonlymphoblastic leukemia. It is associated with a poor prognosis. Molecular and cytogenetic findings help differentiating between de novo acute leukemia and blast crisis of chronic myeloid leukemia.
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PMID:[Cytogenetic and clinical features of Philadelphia chromosome positive leukemias]. 170 14

Chronic myelogenous leukemia (CML) is the best understood human cancer. The molecular basis of CML involves activation of a cellular proto-oncogene--ABL. The consequence is to increase tyrosine kinase activity. This results in a marked clonal increase in the myeloid mass. Later on, cellular maturation is blocked and the decrease eventuates in acute leukemia. Abnormalities of other proto-oncogenes or antioncogenes, like P53, may be involved in leukemia progression. Treatment of CML involves chemotherapy and, more recently, interferon. Whether this treatment prolongs survival or increases the likelihood of cure is unknown but either result seems unlikely. Bone marrow transplants which cure about 50% of persons with CML are most effective when performed in chronic phase.
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PMID:Chronic myelogenous leukemia: molecule to man. 189 3

The effects of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BH-AC) on the cell cycle of murine leukemic cells (L 1210 cells) were compared with those of 1-beta-D-arabinofuranosylcytosine (ara-C), known to be effective for acute leukemia. In a cytokinetic study, a combination of Feulgen microcytofluorometry and tritiated thymidine autoradiography (3H-TdR ARG) was used to measure DNA content and to determine DNA synthesis simultaneously in a single cell. Administration of 200 mg/kg of BH-AC significantly prolonged the survival time of mice bearing L 1210. In addition, the cells in the G1 + S1 phases increased with time, accounting for 94.4 per cent of all cells measured at 48 h after the administration, compared to 73.7 per cent before administration. On the other hand, following the administration of 86 mg/kg of ara-C (equivalent to 200 mg/kg of BH-AC), the percentage of cells in the S1 + S2 phases increased maximally to 75.9 per cent at 18 h. Cytokinetic studies further showed that BH-AC administration blocks DNA synthesis of the cells in the S-phase for a longer period than does ara-C. These results suggest that the prolonged inhibition by BH-AC on DNA synthesis allows cells to accumulate in the S-phase to a greater degree.
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PMID:Cytokinetic study on the effects of N4-behenoyl-1-beta-D-arabinofuranosylcytosine on murine leukemic cells L 1210: a comparison with the effects of 1-beta-D-arabinofuranosylcytosine. 258 Jul 70

Two patients with acute nonlymphocytic leukemia (ANLL) who had normal karyotypes at diagnosis and developed the Philadelphia (Ph) translocation during leukemia relapse are described in this report. Patient 1 relapsed with Ph-positive acute leukemia, FAB classification M1. The Ig heavy chain locus and T cell receptor gamma and beta genes of relapse cells from this patient were all found to be germline configuration confirming the diagnosis of M1 acute leukemia. Patient 2 displayed a complex karyotypic evolution leading to Ph-positive M4 relapse. Ph-positive relapse specimens from both patients expressed P185BCR-ABL protein and RNA gene products that were identified serologically and by polymerase chain amplification of the BCR-ABL RNA junction. In vitro derived myeloid cell lines from relapse M1 leukemia cells of patient 1 also expressed the P185BCR-ABL protein. In two described patients, late appearance of the Ph translocation that encodes P185BCR-ABL coincided with relapse of acute leukemia. We conclude that P185BCR-ABL may be a strong indicator of Ph-positive acute leukemias.
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PMID:P185BCR-ABL in two patients with late appearing Philadelphia chromosome-positive acute nonlymphocytic leukemia. 268 76

The vast majority of pediatric RBC hypoplastic anemias are accounted for by red blood cell aplasia associated with chronic hemolysis, Diamond-Blackfan anemia, and transient erythroblastopenia of childhood. However, other causes of hypoplastic anemia occur in children, and some of these are similar to what is seen in adult RBC aplasia. For example, it has been reported that a 5-year-old girl with an aregenerative anemia had a thymoma and later developed pancytopenia. RBC aplasia also has been seen in children receiving anticonvulsant drug therapy, children recovering from severe protein malnutrition, children with hepatitis, and in children with leukemia during maintenance therapy. In addition, it is not uncommon for pediatric hematologists to observe children with RBC aplasia where there is no obvious diagnosis, although many are considered to be variants of Diamond-Blackfan anemia. Several important questions about RBC hypoplastic anemias in children need to be resolved; it is hoped that this will be accomplished in the next decade. Do RBC hypoplastic crises associated with hemolytic anemia occur with viral infections other than HPV? What is the cellular pathophysiology in DBA and TEC? Does the apparent heterogeneity of these disorders reflect limitations of laboratory techniques or are we looking at several different diseases? Is acute leukemia a real complication of Diamond-Blackfan anemia? Is TEC a completely benign entity or will we see other long-term problems in these children? Is the incidence of TEC actually increasing? Will TEC-like problems be seen in other aged children? As a case in point, we recently observed a 16-year-old girl who presented with pure RBC aplasia that required RBC transfusion support for 5 months; she also received prednisone therapy. After 7 months, however, this young lady had a spontaneous remission, and now 4 years later she is normal and free of any hematologic abnormalities. This was a most unusual event in our experience and, in view of the apparent increasing incidence of TEC in young children, we queried whether we were observing an adolescent equivalent of this disorder. During the next several years the answer to this and the other questions posed herein should be available.
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PMID:Diagnosis and management of red cell aplasia in children. 312 94

Mutants and fusion products of the c-abl gene were used to define some of the molecular requirements for rapid plasmacytoma (PC) and pre-B-lymphoma induction in pristane-treated N-myc transgenic BALB/c mice. A-MuLV induced PCs in 21 of 25 mice with a mean post-pristane latency period of 46 +/- 9 days, compared to 134 +/- 25 days in controls exposed to pristane alone. delta XB, a mutant of type IV c-abl with a deletion of the SH3 domain, was equally effective in inducing PCs in 7 of 7 mice with a latency period of 49 +/- 7 days, indicating that gag sequences are not required for rapid PC induction. The delta XB delta Nar mutant that carried a large C-terminal deletion in addition showed only a negligible activity, if any, suggesting that PC acceleration requires the C-terminal domain in the same way as lymphoid transformation and in contrast to fibroblast transformation. BCR-ABL fusion constructs encoding an 185-kDa protein as in acute leukemia, or a 210-kDa protein as in chronic myelocytic leukemia (CML), did not accelerate pristane-induced PC development in the N-myc transgenic mice, in contrast to their known ability to immortalize lymphoid cells in vitro. Only one of 14 non-transgenic littermates developed a pre-B lymphoma after A-MuLV infection, and none of 10 normal littermates infected with delta XB virus developed a construct-carrying tumor. This result suggests that PC acceleration is due to co-operative interaction of the N-myc transgene and activated abl. Infection of N-myc transgenic bone marrow or spleen cells with A-MuLV in vitro led to the outgrowth of pre-B lymphomas after transplantation to pristane-treated BALB/c recipients. The lymphoma-inducing activity of A-MuLV depends on its high titer, since diluted A-MuLV or the lower-titered delta XB induced only PCs under the same conditions. The v-abl, delta XB and BCR-ABL-carrying viruses generated immortalized lymphoblastoid lines in vitro, regardless of the presence of the N-myc transgene, suggesting that lymphoid transformation is a direct function of appropriate abl sequences in contrast to PC acceleration.
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PMID:Molecular requirements for rapid plasmacytoma and pre-B lymphoma induction by Abelson murine leukemia virus in myc-transgenic mice. 801 9

Cytogenetic analysis of a pediatric patient with T-cell acute lymphoblastic leukemia (T-ALL) revealed a mosaic karyotype, 47,XX,+17,t(11;14)(p13;q11)/47,XX,+17,t(9;22)(q34;q11),t(11;14) (p13;q11). DNA blot analysis was used to examine the break-point within the BCR gene on chromosome 22 and showed that the breakpoint occurred within the 20-kb minor breakpoint cluster region (m-bcr) located within the first intron of the BCR gene. Immunoprecipitation analysis demonstrated that the leukemic cells expressed the P185 BCR-ABL protein tyrosine kinase. P185 BCR-ABL has previously been shown to be expressed in most cases of Ph+ acute leukemia of myeloid and B-progenitor origin. Here, we demonstrate for the first time that P185 can also be expressed in the T-cell lineage. DNA blot hybridization was also used to characterize the t(11;14) translocation. This showed rearrangement on chromosome 11 within the T-ALLbcr region, upstream of the RBTN-2 gene. Polymerase chain reaction revealed the presence of RBTN-2 transcripts in the leukemic cells. Finally, comparison of the T-ALLbcr, BCR-ABL, IGH, TCR beta and gamma gene rearrangements in leukemic cells obtained at the time of diagnosis and at first relapse showed that relapse occurred in a leukemic clone indistinguishable from the major Ph+ clone involved at diagnosis. Together, these data support a multistep pathogenesis in which the Philadelphia (Ph) chromosome translocation appeared subsequent to the +17 and t(11;14) and imparted a growth advantage over the Ph-negative cells that carried these abnormalities.
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PMID:Simultaneous expression of RBTN-2 and BCR-ABL oncogenes in a T-ALL with a t(11;14)(p13;q11) and a late-appearing Philadelphia chromosome. 803 4

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

We focused on biological characteristics of Philadelphia chromosome-positive acute leukemia (Ph+ AL) and treated those patients with BHAC-DMPV induction chemotherapy. After obtaining complete remission, we attempted to treat with allogeneic bone marrow transplantation, while those without suitability for marrow transplantation were treated with alpha-interferon (IFN-alpha), in order to obtain prolong remission status. Chromosomal and molecular analyses, including BCR rearrangement and BCR -ABL mRNA, before and after IFN-alpha treatment demonstrated a recovery of normal hematopoiesis by the treatment of INF-alpha, however, suppressive effect for the blast cells by IFN-alpha was insufficient. To clarify the mechanism of IFN-alpha on the Ph+ leukemia cells, we studied expression of interferon stimulated genes (ISGs). However, an association between expression of ISGs and therapeutic effectiveness was not evident. Although, the exact anti-neoplastic mechanism of IFN-alpha is not established yet, our study demonstrated the possibility for utilization of IFN-alpha in some Ph+ AL patients as a maintenance therapy to obtain long survivals. Therefore, studies using a large number of patients with Ph+ AL should be performed, in order to establish induction and maintenance therapies reflecting biological characteristics of Ph+ AL.
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PMID:[Molecular diagnosis and therapeutic strategy for Philadelphia chromosome-positive acute leukemia]. 815 46


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