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)

Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) is a malignant disorder characterized by a poor prognosis. In recent years hematopoietic growth factors have been used to recruit myeloid leukemia blasts into the proliferative phase of the cell cycle and as supportive agents, both with cytotoxic regimens and in the setting of bone marrow transplantation. This approach prompted us to investigate whether myeloid growth factors have a role in Ph1 positive ALL. To do this, we utilized two newly established Ph1-positive cell lines, Z-119 and Z-181. Both lines have L2 morphology, ultrastructural characteristics of lymphoblasts and typical B-lineage surface markers identical to those observed in the two Ph1-positive ALL patients from whom they were derived. In addition, a single rearranged immunoglobulin heavy-chain gene (JH) band was found in both cell lines by Southern blot analysis, confirming B-cell clonality. Cytogenetic analysis of the two lines revealed t(9;22). Polymerase chain reaction (PCR) amplified cDNA from both Z-119 and Z-181 cells revealed an e1--a2 BCR-ABL junction, and p190BCR-ABL protein was detected in them by the immune complex kinase assay. Both cell lines produce interleukin (IL)-1 beta, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), but neither IL-1 beta, G-CSF, their corresponding antibodies and inhibitory molecules, nor GM-CSF, affected the cell lines' growth. However, GM-CSF neutralizing antibodies inhibited Z-181 but not Z-119 colony formation in a dose-dependent fashion by up to 77% and addition of GM-SCF reversed this inhibitory effect. Receptor studies with radiolabeled GM-CSF demonstrated specific binding to Z-181 but not to Z-119 cells, and Scatchard analysis revealed that Z-181 cells express high-affinity GM-CSF receptors. Furthermore, PCR analysis showed that Z-181 but not Z-119 bears the transcript for the GM-CSF receptor. Finally, studies using PH1-positive ALL patients' marrow cells revealed similar data. In 3 of 8 samples we detected significant concentrations of GM-CSF (7.5-13 pg/2 x 10(7) cells) and in 2 of 3 cases GM-CSF significantly stimulated Ph1-positive ALL colony proliferation. These data suggest that Ph1-positive ALL cells may produce GM-CSF, express GM-CSF receptors and thus show a proliferative response to this cytokine.
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PMID:Role of granulocyte-macrophage colony-stimulating factor in Philadelphia (Ph1)-positive acute lymphoblastic leukemia: studies on two newly established Ph1-positive acute lymphoblastic leukemia cell lines (Z-119 and Z-181). 860 Jan 66

Although the Philadelphia chromosome (Ph1) has been identified as an adverse prognostic factor in acute lymphoblastic leukemia (ALL), little is known about the incidence and clinical course of relapsed Ph1-positive ALL in children. The incidence was determined by screening of 170 consecutive children with first bone marrow relapse of ALL using the reverse transcriptase-polymerase chain reaction (RT-PCR) and comparison, with cytogenetic analysis. Among these 170 children, 20 (12%) were found to be BCR-ABL-positive, representing a rate that is about three times higher than that reported for newly diagnosed ALL. Ten of the cases were identified by RT-PCR only. In none of the 21 patients with T-cell immunophenotypes could an expression of the BCR-ABL mRNA be detected. BCR-ABL positivity was associated with a significantly shorter duration of first remission (P = .0086) and higher white blood cell (P = .0157) and blast cell counts (P = .0304) at relapse diagnosis. All patients were treated according to the ALL-REZ BFM 87 and 90 relapse trials of the BFM Relapse Study Group. The intensive multiagent chemotherapy induced a second complete remission in only 60% of children with BCR-ABL-positive ALL compared with in 91% of those without BCR-ABL expression (P = .0023). The prognosis of BCR-ABL-positive ALL in children is poor, with a probability of event-free survival at 2 years of 8% versus 50% in those without BCR-ABL mRNA or cytogenetic analysis should become part of the routine diagnostic panel for children with newly diagnosed ALL and is fundamental for children presenting with an early bone marrow relapse.
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PMID:Clinical features and outcome of children with first marrow relapse of acute lymphoblastic leukemia expressing BCR-ABL fusion transcripts. BFM Relapse Study Group. 860 44

In Philadelphia chromosome (Ph1) positive leukemias, the BCR gene is fused to the ABL gene. The resulting chimeric BCR-ABL oncoproteins are thought to play a central role in the pathogenesis of these diseases. We previously described two exons that can be spliced alternatively to the second BCR exon in place of the first exon to form minor messages. In this paper, we localize the alternative exons to a 4.1 kb BglII fragment in the 5' region of the large first intron of the BCR gene. This genomic structure is of interest because of its analogy to the organization of the ABL gene and because this part of the gene is not affected by the breakpoints occurring in Ph1-positive acute lymphoblastic leukemia (ALL). Using the reverse transcriptase-polymerase chain reaction (RT-PCR), we detected the alternative messages in all cases of chronic myelogenous leukemia (CML) tested, including seven samples in the chronic phase, five in the accelerated phase and nine in the acute phase, as well as in the majority of other samples studied. These findings suggest a functional role for the variant transcripts.
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PMID:The first intron of the BCR gene contains two minor alternative exons. 863 66

Two types of markers, namely the clone-specific markers including T-cell receptor (TCR) gamma, TCR delta, and Ig heavy-chain (IgH) gene rearrangements, and malignancy-specific fusion gene mRNA such as SIL-TAL-1, BCR-ABL, and HRX-partner genes, were investigated by molecular biology techniques in 65 Chinese patients with acute lymphoblastic leukemia (ALL). In combination, these markers were informative among 96% of patients. Minimal residual disease (MRD) was followed up in 23 of these patients with available materials over a period varying from 8 to 54 months with at least one leukemia-specific probe. In most children, MRD was decreased continuously to an ultimately undetectable level within 6 to 12 months after remission induction therapy. One patient exhibited low-level residual leukemic cells for 4 years before the MRD turned negative. Another patient remained in complete remission for 45 months, although a positive signal was detected at 34 months using TCR delta probe, but was negative with a TCR gamma marker which was positive at presentation. In three patients who relapsed, MRD either persisted through the clinical course or became positive and eventually increased 3-11 months before clinical relapse. These data suggested that the combined use of multiple gene markers is a valuable tool for the PCR-based MRD detection, since it can cover most ALL patients. Furthermore, long-term follow-up of MRD is helpful for determining the dosage as well as the period of maintenance chemotherapy and for predicting impending relapse.
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PMID:Long-term follow-up of minimal residual disease in childhood acute lymphoblastic leukemia patients by polymerase chain reaction analysis of multiple clone-specific or malignancy-specific gene markers. 864 Jul 18

The Philadelphia chromosome in cells of patients with chronic myeloid leukemia and acute lymphoblastic leukemia can be detected by reverse transcriptase-polymerase chain reaction (RT-PCR). We have tested two new methods for this purpose. For diagnostic purposes, three different BCR-ABL translocations (b3a2, b2a2 and ela2) can be detected in a multiprimed, one step PCR reaction. By using a competitor DNA construct and a two-step, nested PCR reaction, a quantitative measure of the number of specific BCR-ABL transcripts can be estimated. We tested five patients with chronic myeloid leukemia. All of them showed positive BCR-ABL translocations in the diagnostic test. Patients with other myeloproliferative disorders, used as controls, were all negative. Quantitative measurements of specific BCR-ABL mRNA showed that as few as ten transcripts could be quantified in the assay. The analysis showed that coefficients of variation between 15% and 30% were obtained for specific transcripts per micrograms RNA, whereas specific BCR-ABL per normal ABL showed a coefficient of variation of 10%. These new methods to detect BCR-ABL translocation by RT-PCR should provide easy and sensitive diagnosis, and possibilities of monitoring residual disease or relapse.
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PMID:[Diagnosis and follow-up in chronic myeloid leukemia. Detection and quantification of specific transcripts with the help of reverse transcriptase-polymerase chain reaction]. 864 73

One hundred and forty-three patients with p210 BCR-ABL-positive leukemia were studied for coexpression of p190 BCR-ABL mRNA. p190 mRNA was detected in 14 of 16 (88%) patients with chronic-phase chronic myeloid leukemia (CML) at diagnosis, in 10 of 10 (100%) CML patients in blast crisis, in 75 of 107 (70%) CML patients receiving interferon-alpha (IFN-alpha), and 10 of 10 (100%) patients with p210 BCR-ABL-positive acute lymphoblastic leukemia (ALL). Neither p210 nor p190 BCR-ABL transcripts were detected in normal healthy adults (n = 20). The numbers of p190 transcripts determined by competitive PCR in patients with CML were low compared with the numbers of p210 transcripts. The median numbers of p210 and p190 transcripts per unit volume of cDNA in positive samples were 1.0 x 10(5) (range, 15 to 1.4 x 10(6)) and 10 (range, 10 to 2.9 x 10(3)), respectively. The numbers of p190 and p210 transcripts were significantly correlated in individual samples (r = .65, P < .001). The median number of p210 BCR-ABL transcripts was significantly lower in samples negative for p190 BCR-ABL transcripts than in samples in which p190 BCR-ABL transcripts were identified (3.1 x 10(3)[n = 73] v 1.0 x 10(5)[n = 115]; P < .0001). The median ratio of p190 to p210 BCR-ABL mRNA was not significantly different between chronic phase CML (1.9 x 10(-4)) and CML in blast crisis (1.7 x 10(-4)). The median ratio in p210 ALL was also low (1.9 x 10(-3)) but significantly higher than that of CML. We conclude that pl90 BCR-ABL transcripts are frequently present at a low level in p210 BCR-ABL-positive leukemias. p190 mRNA may arise through alternative or missplicing and its presence is probably of no pathogenetic significance.
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PMID:p190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias. 865 35

Chronic myelogenous leukemia (CML) can sometimes present in lymphoid blast phase (L-BP), and can be difficult to distinguish from Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Some have suggested that the determination of cell lineages involved by the Ph chromosome may be used for distinguishing CML presenting in L-BP (presumably multilineage disease) from Ph+ ALL (presumably lymphoid-restricted), although others have suggested the term 'stem cell ALL' for the multilineage process. Because it has been difficult to perform lineage studies of the Ph chromosome, we investigated the use of fluorescence in situ hybridization (FISH) with probes for BCR (on chromosome 22) and ABL (on chromosome 9) to study lineage involvement in Ph+ lymphoblastic malignancies. We analyzed routine blood and marrow specimens from eight patients who presented with Ph+ lymphoblastic leukemia and found that FISH recognized the 9;22 translocation, distinguished between the two common molecular variants, and readily identified multilineage vs lymphoblast-restricted disease. In our series, four patients had multilineage and four had lymphoblast-restricted disease. Multilineage disease was associated with morphologic features of CML at diagnosis and/or reversion to chronic phase CML after treatment leading us to consider it as CML presenting in L-BP. Patients with lymphoid-restricted disease lacked such findings. The survival of three of our four patients with multilineage disease was prolonged, at 25, 28+, and 126+ months, and when data from our entire series are added to those of 18 previously reported cases that were studied for lineage involvement (reviewed in Leukemia 1993; 7: 147), the difference in overall survival between patients with multilineage and lymphoblast-restricted disease is significant (median overall survival of 47 months vs 8 months, respectively; P=0.013, log rank). Our findings illustrate that FISH analysis can be used to recognize lineage involvement in patients presenting with Ph+ lymphoblastic malignancies, and they provide further support to the notion that multilineage and lymphoblast-restricted disease are distinct clinically as well as biologically.
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PMID:Lineage involvement by BCR/ABL in Ph+ lymphoblastic leukemias: chronic myelogenous leukemia presenting in lymphoid blast vs Ph+ acute lymphoblastic leukemia. 865 74

It has recently been shown that the t(12;21)(p13;q22) translocation fuses two genes, TEL on chromosome 12 and AML1 on chromosome 21. We have evaluated the frequency of this newly described translocation in acute lymphoblastic leukemia (ALL), and the feasibility of minimal residual disease (MRD) monitoring by polymerase chain reaction (PCR) amplification of TEL-AML1 transcripts. Thirty-nine adult- and 45 childhood-ALLs consecutively diagnosed in a single center were included in this study. TEL-AML1 fusion transcripts were searched for in the 39 adult- and 45 childhood-ALLs for which material was available. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were also studied by PCR in these cases. TEL-AML1 transcripts were found in 8 out of 35 (23%) childhood B-cell precursor ALLs (BCP-ALLs). TEL-AML1 transcripts were detected in only 1 of 31 adult BCP-ALLs (P = .04, Fisher's exact test). Nevertheless, in this adult case, TEL-AML1 transcripts were found at a low level in 2 of 3 different samples. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were found in 12, 3, and 1 cases of 31 adult BCP-ALLs, and in 1, 2, and 1 cases of 35 childhood BCP-ALLs, respectively. TEL-AML1 transcripts were never found associated with any other fusion transcripts. Taken together, the four types of chimeric transcripts were detected in 12 of 35 (34%) childhood BCP-ALL cases. No TEL-AML1 transcripts were detected in 11 T-cell ALLs (4 adults and 5 children), nor in 2 B-cell (slg+) ALLs. MRD was evaluated in 21 samples collected in 9 TEL-AML1+ childhood BCP-ALL cases during therapy (median follow-up = 200 days). Of 8 patients evaluated after induction therapy, 4 showed detectable but low levels of MRD. Of 7 patients serially evaluated, only one showed persistence of detectable MRD. This study shows that TEL-AML1 transcripts are frequently detected in pediatric BCP-ALLs and that these transcripts are molecular targets that will simplify the strategy of MRD monitoring in childhood BCP-ALL.
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PMID:TEL-AML1 fusion RNA as a new target to detect minimal residual disease in pediatric B-cell precursor acute lymphoblastic leukemia. 870 88

Interleukin-7 (IL-7) stimulates the proliferation of normal and leukemic B and T cell precursors and T lymphocytes. Activation of the JAK/STAT pathway has been implicated in IL-7R signaling. We investigated which STAT complexes are formed upon stimulation of B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells with IL-7. Gel retardation assays with STAT-binding oligonucleotides showed that IL-7 induces the formation of two major STAT complexes in BCP-ALL cells. Supershifts with anti-STAT antibodies identified these as STAT1 and STAT5 complexes. This pattern of STAT activation was seen in all BCP-ALL cases that respond to IL-7 in proliferation assays. IL-7 also induced STAT/DNA binding in BCP-ALL cases that failed to proliferate in response to IL-7, suggesting that the ability of IL-7R to activate the JAK/STAT pathway per se is not sufficient for proliferation induction. To determine the contribution of the cytoplasmic domain of the IL-7 receptor alpha chain (IL-7R alpha) to activation of STAT proteins, transfectants of the murine pro-B cell line BAF3 were made that express chimeric receptors consisting of the extracellular domain of human granulocyte colony-stimulating factor receptor (G-CSF-R) and the transmembrane and intracellular domains of human IL-7R alpha. Activation of the chimeric G-CSF-R/IL-7R alpha with G-CSF resulted in a full proliferative response and induced the phosphorylation of JAK1 but not JAK2. Major STAT complexes activated by G-CSF-R/IL-7R alpha contained STAT1 or STAT5, while some formation of STAT3-containing complexes was also seen. These findings establish that STAT1 and STAT5, and possibly STAT3, are activated upon stimulation of precursor B cells with IL-7. The data further indicate that the IL-7R alpha chains are directly involved in the activation of JAKs and STATs and have a major role in proliferative signaling in precursor B cells.
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PMID:Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain. 870 37

Cryptic t(12;21)(p12-13;q22) leading to TEL-AML1 fusion has recently been recognized as the most frequent genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) in Western countries. More recently, we found a similar frequency of this abnormality in Chinese children with ALL in Taiwan. In this study, we assessed further the frequency of TEL-AML1 fusion as well as that of BCR-ABL in Chinese adults with ALL, using reverse transcriptase-polymerase chain reaction assays. Among the 81 cases with newly diagnosed B lineage ALL studied, none had the TEL-AML1 fusion whereas 30 had the BCR-ABL fusion. The lack of cases with the TEL-AML1 fusion together with the high frequency of BCR-ABL fusion could largely account for the poorer outcome of adult ALL as compared with childhood ALL.
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PMID:Lack of TEL-AML1 fusion transcript resulting from a cryptic t(12;21) in adult B lineage acute lymphoblastic leukemia in Taiwan. 875 62


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