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 important advances made in recent years in the therapy of adult ALL have been reviewed. The definition of bad-prognosis patients has been improved and includes those with T-ALL, ABLL, and Ph1+ALL, in addition to those presenting with evidence of extensive disease. In contrast to childhood ALL, induction chemotherapy should include another drug (or drugs) in addition to VCR and prednisolone, and one of the anthracycline drugs (ADR or DNR) has been employed most frequently in this context. Such therapy should result in a CR rate of 70 to 75%. Similar to the experience in childhood ALL, the improvement in haematological response rate has led to an apparent increase in CNS leukaemia, and the need for adequate CNS prophylaxis is stressed. Despite these improvements, the outlook for adults with ALL is not yet as good as it is for childhood ALL. Controlled studies involving large numbers of patients are urgently needed to provide answers to a number of questions. In induction therapy, the use of higher drug dosage, the use of more and other drugs, and the use of an individual patient's risk factors to determine drug dosage, must be assessed. The benefits of consolidation therapy and the optimal duration and intensity of maintenance therapy have yet to be established. Methods of CNS prophylaxis other than cranial irradiation and IT MTX must be carefully studied. These important questions require that adult patients with ALL should be concentrated in centres capable of providing optimal overall care and, at the same time, able to conduct the necessary clinical trials.
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PMID:The management of adult acute lymphoblastic leukaemia. 36 95

HSB-2 is a cell line derived from a patient who had T-cell acute lymphoblastic leukemia (T-cell ALL) with a t(1;7)(p34;q34). We used a genomic probe from the T-cell receptor beta (TCR beta) locus (7q34) to identify DNA rearrangements in HSB-2. Two rearranged BglII DNA fragments were cloned, and one of these clones was shown to contain the translocation breakpoint on the derivative chromosome I [der(I)]. We used a probe derived from this clone to isolate an unrearranged phage clone encompassing the breakpoint at Ip34. The restriction map of this clone was compared to the published maps of known protooncogenes located at Ip32-34. By restriction mapping, Southern blot analysis, and DNA sequencing we showed that the translocation breakpoint on chromosome I is located within the first intron of the LCK gene. The LCK gene codes for p56lck, a member of the SRC family of cytoplasmic tyrosine protein kinases. There are two classes of LCK transcripts (type I and type II), each expressed from a distinct promoter, and each having a unique 5' untranslated region (UTR); the protein coding regions of the two classes are identical. The breakpoint in the t(1;7) separates the two LCK promoters and juxtaposes the constant region of the TCR beta locus with the proximal promoter and with the protein-coding region of the LCK gene on the der(I) chromosome.
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PMID:The LCK gene is involved in the t(1;7)(p34;q34) in the T-cell acute lymphoblastic leukemia derived cell line, HSB-2. 166 80

The Ph chromosome was the first specific karyotype abnormality associated with a particular neoplastic disease in humans. For many years it was suspected that chromosome abnormalities might cause cancer by alteration of specific genes or their expression. Significant recent developments in our understanding of the molecular consequences of the Ph translocation strengthen that assumption. The Ph translocation generates a hybrid gene consisting of 5' regulatory, promotor, and exon sequences of the bcr gene on chromosome 22 fused to 3' exons and polyadenylation/termination sequences of the ABL proto-oncogene from chromosome 9. It is well established that fusion of bcr and abl genes plays a crucial role in the pathogenesis of CML and ALL. Molecular methods can therefore be used as diagnostic tools to detect the Ph chromosome. Presently, the model of oncogenesis provided by our knowledge of how the abl proto-oncogene becomes activated as a result of the Ph translocation is one of the clearest models of oncogene activation. Despite the progress made, many areas remain to be explored. One important question is, how the hybrid protein is involved in leukemia. Research aimed at investigating the normal function of abl and bcr may be important in efforts to understand their abnormal functioning in leukemia and to increase our understanding of the disease.
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PMID:Molecular insights into the Philadelphia translocation. 205 Jun

We have previously described a patient in whom the breakpoint occurred within the first intron of the BCR gene and have cloned the 9q+ and 22q- junctions. We have now determined the nucleotide sequence around the breakpoints on both translocation products from this patient as well as the corresponding regions from the normal chromosomes 9 and 22. We have compared the sequence with that of the breakpoint regions in the Ph1-positive leukemic patients in order to check for the presence of conserved motifs. A + T-rich sequences and ALU repeat elements are the only sequence characteristics which appear to be very common around translocation regions. The chromosome 9 ABL sequences at or adjacent to the breakpoints present in the 22q- product show homology to the consensus ALU sequence while the chromosome 22 sequences do not, suggesting a non-homologous recombination mechanism. While no sequences are deleted, there is a two-base-pair "homology" at the junction. Therefore, staggered breaks followed by ligation and repair could be part of the mechanism involved in the process of translocation in some cases of Ph1-positive ALL.
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PMID:Characterization of the translocation breakpoint sequences in Philadelphia-positive acute lymphoblastic leukemia. 208 18

Chronic myeloid leukaemia (CML) is an excellent model for the study of molecular rearrangements caused by a cytogenetic anomaly associated with a disease. The formation of a Philadelphia chromosome by translocation between chromosomes 9 and 22 provokes the breaking and migration of a cellular oncogen (ABL), located in the 9q34 region, towards chromosome 22 and the 22q11 region where the PHL gene is situated. This gene is broken in the bcr area the rearrangements of which are specific to CML. The ABL and PHL genes fragments fuse together, creating a new hybrid gene which is transcribed into an 8.5 kilobase messenger RNA specific to CML. This RNA is translated into a 210 kilodalton protein whose abnormally high tyrosine kinase activity seems to contribute to the development of the disease. Genetic engineering techniques improve our understanding of CML molecular mechanisms and can be very useful to clinicians as they permit the diagnosis of CML in some cases devoid of chromosomal markers, and the detection of a possible relapse in marrow-grafted patients with a much greater sensitivity (one in 100,000 cells) than that of cytogenetics.
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PMID:[Chronic myeloid leukemia: from cytogenetics to molecular biology]. 209 36

The Philadelphia (Ph) chromosome usually results from the t(9;22), which causes the physical association of the BCR1 and ABL genes and their function as a single new gene. This precise genomic mutation probably has a significant role in the development of leukemia in humans, but that leukemia may take several forms: chronic myeloid leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, and essential thrombocythemia; CML also transforms to a lymphoid or myeloid acute phase. Two models are considered with regard to determinants of this variable hematologic expression of BCR-ABL. The first is variation in the breakpoint site of BCR1. Two breakpoint sites, M-BCR and m-BCR, are known, and their occurrence shows a nonrandom association with the different forms of leukemia. The precise position of the breakpoint within M-BCR may also be important. The second model concerns the role of other genes in determining the leukemic form shown by BCR-ABL. Results are reviewed of a patient who entered blast crisis CML and whose leukemic clones involved ten genetic loci with known leukemic associations. Many of these were probably genetic variants that allowed leukemic proliferations following the initiation of blast crisis. The multiplicity of these genes may obscure the prime determinant of blast crisis, which is unknown at the present time.
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PMID:The variable hematologic expression of the BCR-ABL genomic mutation and its possible determinants. 279 Jul 50

A probe derived from the 3' region of the BCR gene (breakpoint cluster region gene) detects four distinct loci in the human genome. One of the loci corresponds to the complete BCR gene, whereas the others contain a 3' segment of the gene. After HindIII cleavage of human DNA, these four loci are detected as 23-, 19-, 13-, and 9-kilobase-pair fragments, designated BCR4, BCR3, BCR2, and BCR1, respectively, with BCR1 deriving from the original complete BCR gene. All four BCR loci segregate 100% concordantly with human chromosome 22 in a rodent-human somatic cell hybrid panel and are located at chromosome region 22q11.2 by chromosomal in situ hybridization. The BCR2 and BCR4 loci are amplified in leukemia cell line K562 cells, indicating that they fall within the amplification unit that includes immunoglobulin lambda light chain locus (IGL) and ABL locus on the K562 Philadelphia chromosome (Ph1); additionally, in chronic myelogenous leukemia-derived mouse-human hybrids retaining a Ph1 chromosome in the absence of the 9q+ and normal chromosome 22, BCR2 and BCR4 loci are retained, whereas the 3' region of BCR1 and the BCR3 locus are lost, indicating that BCR3 is distal to BCR1 on chromosome 22. Similarly, in mouse-human hybrids retaining a Ph1 chromosome derived from an acute lymphoblastic leukemia-in the absence of the 9q+ and 22, only BCR2 and BCR4 loci are retained, indicating that the breakpoint in this acute lymphoblastic leukemia, as in chronic myelogenous leukemia, is proximal to the BCR1 3' region, but distal to the IGLC locus and the BCR2 and BCR4 3' loci. Thus, the order of loci on chromosome 22 is centromere----BCR2, BCR4, and IGL----BCR1----BCR3----SIS, possibly eliminating BCR2 and BCR4 loci as candidate targets for juxtaposition to the ABL gene in the acute lymphoblastic leukemia Ph1 chromosome.
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PMID:Mapping of four distinct BCR-related loci to chromosome region 22q11: order of BCR loci relative to chronic myelogenous leukemia and acute lymphoblastic leukemia breakpoints. 311 59

A great deal of information has emerged over the past decade regarding the gene structures and corresponding protein products of the cellular and transformation-associated forms of the ABL tyrosine kinase family. Many reports have also detailed the biological effects of these proteins (particularly the viral ABL forms) on a broad range of cell types. However, in spite of all these research efforts, the precise role of the ABL gene in normal and neoplastic growth remains to be determined. To elucidate the mechanism of action of normal and altered ABL proteins, it is imperative to identify their relevant cellular substrates and establish the role of the ABL target proteins in transformation and normal cellular growth. The availability of temperature-sensitive ABL proteins, coupled with the use of sensitive anti-phosphotyrosine antibodies, should be useful in this respect. Purification of enzymatically active, intact forms of the ABL proteins produced in insect cells by employing baculovirus expression vectors should permit direct comparison of the biochemical properties and tertiary structures of the various members of the ABL protein kinase family. Such studies will aid in understanding the nature of the alteration of ABL which results in the activation of its transforming potential. Furthermore, the availability of purified ABL proteins should permit examination of interactions of ABL with other growth-regulatory proteins, such as growth factor receptors. It has been shown that transformation-associated ABL proteins interact with the IL-3, IL-2 and GM-CSF growth-factor pathways. These and other components of the cellular signalling pathways are potential ABL targets. The elucidation of ABL function by a variety of approaches such as those described above will ultimately aid in the development of far-reaching therapeutic treatments for at least two forms of human leukaemia: Ph positive CML and Ph positive ALL.
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PMID:Role of the ABL oncogene tyrosine kinase activity in human leukaemia. 333 51

The Ph chromosome is the hallmark of CML, where it is found in more than 90% of the cases. Cytogenetically, it usually results from a t(9;22)(q34;q11). The Ph arises in a stem cell and in chronic phase is found in all haematopoietic cell lineages, although it causes only increased granulopoiesis, and sometimes increased thrombopoiesis; furthermore blast crisis may occur in all differentiative patterns of the pluripotent stem cell. Recently, molecular investigations of Ph positive CML cases have revealed a consistent genomic recombination between two genes, BCR on chromosome 22 and the ABL oncogene. The latter is translocated from 9q34, its normal site, to the 22q- or Ph chromosome. This molecular rearrangement expresses a unique 8.5 kb BCR-ABL hybrid mRNA transcript, that encodes an altered BCR-ABL protein of approximately 210 kD with enhanced in vitro tyrosine kinase activity. The breakpoints on chromosome 22q- are clustered in a 5 kb DNA fragment, allowing their study using Southern blot analysis. Cytogenetic variant forms of the Ph translocation involving three or more chromosomes are found in about 5% of the cases. Southern blot and in situ hybridization studies have demonstrated that these variants are cytogenetically more complex than the standard t(9;22) but molecularly they show the same essential genomic recombination. This is also true for a small number of cases of Ph negative CML. Clonal progression, indicated by the presence of clonal, non-random chromosome abnormalities, in addition to the Ph is rare during chronic phase but is found in 80% of blast crisis. These additional aberrations may precede BC by weeks or months and have therefore a clear prognostic value. Ph is not restricted to CML, since it is also found in ALL (20% of adult cases) and rarely in AML. Ph in acute leukaemia is cytogenetically indistinguishable from Ph in CML, but molecular studies have shown that in 50% of the cases the breakpoint on chromosome 22 is different from the very consistent and characteristic breakpoint in CML. Nevertheless genomic recombination takes place that results in a novel ABL protein at least in some of the cases. Despite extensive cytogenetic and molecular investigations, the mechanisms underlying the formation of the Ph as well as the pathogenesis of Ph positive CML are still unknown but are now the object of intensive research.
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PMID:Chromosome abnormalities in CML. 333 58

Residual leukemic cells are detectable at frequencies as low as 1 in 10(6) normal cells in patients with Philadelphia chromosome/BCR-ABL-positive leukemias in complete remission (CR) using reverse-transcriptase polymerase chain reaction (RT-PCR) with specific nested primers. The level of minimal residual disease (MRD) in the bone marrow (BM) and the peripheral blood (PB) may favor one of the two as the source for an autologous graft. In order to quantify MRD with RT-PCR we analyzed patients ficolled cells after limiting logarithmic dilutions in normal ficolled buffy-coat cells. In six patients with BCR-ABL-pos ALL who were in CR by conventional criteria (5 in CR1 and 1 in CR2), we studied a total of nine paired BM and PB samples prior to scheduled ABMT. A positive RT-PCR signals was detectable in all samples up to dilutions ranging from 1:10(1) to 1:10(3) in PB, and at higher titers ranging from 1:10(3) to 1:10(5) in the BM. The BM titers exceeded the corresponding PB titers in all nine sample pairs by at least 1 log. The mean difference was 1.55 log (geometric mean, n = 9) and is statistically significant (p < 0.03). We conclude that residual leukemia in BCR-ABL-positive ALL preferentially locates in the BM compartment, and we assume that PB may yield autologous grafts with significantly less leukemic contamination.
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PMID:In patients with BCR-ABL-positive ALL in CR peripheral blood contains less residual disease than bone marrow: implications for autologous BMT. 751 36


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