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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two patients with Philadelphia chromosome-positive acute lymphoblastic leukemia showed novel variants of the chimeric bcr-abl mRNA. The bcr-abl breakpoint region on cDNA derived from the chimeric mRNA was amplified using the polymerase chain reaction (PCR). Sequence analysis of the breakpoint-containing fragment showed that in both patients exon a2 of the abl gene was deleted, giving rise to an in-frame joining at the mRNA level of 5' bcr sequences to the abl exon a3. These findings were confirmed by Southern blot analysis and cloning of chromosomal DNA. Protein studies showed a bcr-abl protein with heightened tyrosine kinase activity in blast cells of both patients: one of the P190 type, the other of the P210 type. The significance of these findings and the role of this new type of translocation in the disregulation of the abl gene are discussed.
Leukemia 1990 Jun
PMID:A novel variant of the bcr-abl fusion product in Philadelphia chromosome-positive acute lymphoblastic leukemia. 793 77

A modified polymerase chain reaction (PCR) procedure was used to study the expression of bcr-abl fusion transcripts following allogeneic bone marrow transplantation (BMT) for Philadelphia chromosome (Ph1) positive acute and chronic leukemias. The technique was applied to RNA preparations of peripheral blood and bone marrow cells from 10 patients with chronic myelogenous leukemia (CML) and one patient with acute lymphoblastic leukemia (ALL), all of whom had undergone allogenic BMT and were in clinical and cytogenetic remission. Pre-BMT samples available for eight of 11 patients contained detectable bcr-abl fusion products serving as a baseline for comparison to post-BMT studies. Six patients showed no PCR-detectable bcr-abl transcripts in each of several serial analyses post-BMT (1-36 months post-BMT). The remaining five patients demonstrated various patterns of bcr-abl transcript expression after transplantation. In three patients, bcr-abl transcripts persisted for up to 3 months post-BMT but subsequently were undetectable. Molecular relapse was observed 3 and 6 months post-BMT in the remaining two patients whose earlier post-BMT samples showed no bcr-abl fusion transcripts. No bcr-abl transcripts were detected in subsequent samples from both of these patients 6 months and 1 year post-BMT, respectively. These data confirm that Ph1 carrying cells expressing the bcr-abl fusion mRNA may persist or recur for several months following BMT in the absence of clinical and cytogenetic relapse. The significance of these observations is discussed with respect to results reported recently by others using similar techniques.
Leukemia 1990 Aug
PMID:Expression of bcr-abl fusion transcripts following bone marrow transplantation for Philadelphia chromosome-positive leukemia. 220 32

Among 77 unselected patients with chronic myelogenous leukaemia (CML), 70 had Philadelphia chromosome (Ph1) in blood cells. Extra chromosomal abnormalities were noted in 4%, 55% and 78% of Ph1-positive patients in chronic phase, accelerated phase and acute blast crisis, respectively. Rearrangement of the bcr was detected in 46 of 47 Ph1-positive patients studied and also in three of five Ph1-negative ones. The locations of the breakpoints were mapped to one of four zones of the bcr in 45 patients. The median duration from diagnosis of CML to onset of acute blast crisis was not significantly different between the two groups of patients with breakpoints in the 5' portion (34 months), and in the 3' portion (39 months) of the bcr. In addition, the locations of the breakpoints within the bcr did not change as the disease progressed in the six patients who had DNA analysed both in the chronic phase and subsequently in transformation. In one of them, an additional aberrant band which was not present in the beginning of the acute phase was detected in blood cells taken 2 months later. It is suggested from the studies that transformation of CML may not be related to alterations within the bcr.
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PMID:Chromosome and bcr rearrangement in chronic myelogenous leukaemia and their correlation with clinical states and prognosis of the disease. 220 98

Knowledge of the level of commitment of the target cell in hematological malignancies may have important therapeutic and prognostic implications. Cell lineage involvement was investigated in two cases presenting with acute lymphoblastic leukemia diagnosed on clinical and immunological findings and having the Philadelphia translocation t(9;22)(q34;q11). DNA from cells separated into mononuclear (lymphoid) and granulocytic fractions was hybridized with Philadelphia breakpoint-specific probes. This revealed that the breakpoint giving rise to the Philadelphia chromosome in case 1 was within the major breakpoint cluster region and in case 2 was in the first intron of the BCR gene. Rearrangement was found in the lymphoid but not the granulocyte fraction in each case. It is therefore concluded that the target cell for chromosomal change in these cases was a lymphoid committed progenitor cell, irrespective of breakpoint location.
Leukemia 1990 Oct
PMID:First intron and M-bcr breakpoints are restricted to the lymphoid lineage in Philadelphia positive acute lymphoblastic leukemia. 221 72

The Philadelphia translocation results in the expression of a family of chimaeric proteins in which a portion of the bcr protein is fused to c-abl protein. Using antibodies which recognize different portions of the bcr gene and abl gene products we have compared the normal bcr products with their chimaeric counterparts. We first conclude that the enhanced kinase activity of the rearranged bcr-abl products (p210 and p190) is recovered almost exclusively from the cytosolic fraction. This methodology was confirmed by the demonstration that in cells transformed by the Abelson murine leukemia virus (A-MuLV) the gag-abl kinase activity was recovered equally from the membrane and cytosolic fractions, in agreement with previous studies. To determine whether the distribution of kinase activity reflected the bulk distribution of the bcr-abl proteins, in vivo labeling followed by subcellular fractionation was performed. Both normal bcr proteins and the p210 bcr-abl protein were recovered from the cytosolic fraction with little detectable amounts present in other fractions. In vivo labeling was also used to demonstrate that both normal bcr products and the p210 bcr-abl had a relatively long half-life. It is concluded that bcr-abl products, like normal bcr products are located in the cytosolic fraction.
Leukemia 1990 Nov
PMID:BCR-ABL and BCR proteins: biochemical characterization and localization. 223 85

Chronic myelogeneous leukemia (CML) is genetically characterized by fusion of the bcr and abl genes on chromosomes 22 and 9, respectively. In most cases, the fusion involves a reciprocal translocation t(9;22)(q34;q11), which produces the cytogenetically distinctive Philadelphia chromosome (Ph1). Fusion can be detected by Southern (DNA) analysis or by in vitro amplification of the messenger RNA from the fusion gene with polymerase chain reaction (PCR). These techniques are sensitive but cannot be applied to single cells. Two-color fluorescence in situ hybridization (FISH) was used with probes from portions of the bcr and abl genes to detect the bcr-abl fusion in individual blood and bone marrow cells from six patients. The fusion event was detected in all samples analyzed, of which three were cytogenetically Ph1-negative. One of the Ph1-negative samples was also PCR-negative. This approach is fast and sensitive, and provides potential for determining the frequency of the abnormality in different cell lineages.
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PMID:Detection of bcr-abl fusion in chronic myelogeneous leukemia by in situ hybridization. 223 8

Oncogenes are aberrant forms of proto-oncogenes, which are normal cellular genes that participate in cell growth and development; proto-oncogenes contribute to tumor formation when mutations or chromosomal translocation cause them to escape normal controls. Anti-oncogenes, also involved in neoplasm development, normally participate in inhibition of cell growth and proliferation; they become tumorigenic when mutations alter their function. Oncogene or anti-oncogene abnormalities have been characterized for a variety of tumors, with resulting clinical applications. In some forms of leukemia, for example, determining the presence or absence of the bcr-abl gene rearrangement has both diagnostic and prognostic value. The best-studied anti-oncogene is that found in retinoblastoma. Molecular techniques can differentiate the hereditary from the nonhereditary form of this disease and, with hereditary retinoblastoma, predict disease likelihood in family members.
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PMID:Oncogenes and cancer: clinical applications. 225 81

The promoter of the human BCR gene, regulating the transcription of the chimeric BCR/ABL mRNA in leukemia, has been isolated and characterized. A region of 1.1 kb immediately 5' to the transcription start site was analyzed in detail by sequencing, DNase 1 footprinting, gel retardation and functional studies. These experiments localized a minimal promoter to a 650 bp sequence, composed of 270 bp of 5' flanking sequences and 380 bp of exon 1 transcribed sequences. The promoter region includes a TTTAA box, one Sp1 site and a novel protein-binding sequence absolutely necessary for efficient transcription in vivo. Six additional protein-binding regions were identified more to the 5'. Of these, one is found in an inverted repeat in the 3' coding and splice donor region of BCR exon 1.
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PMID:Unique organization of the human BCR gene promoter. 226 70

The diagnosis and classification of leukaemia started with simple morphological examination and now embraces use of special stains, cytochemistry and immunophenotyping. Genetic studies have progressed from karyotyping to detection of genetic changes within genes. The methods described in this chapter are still at an early stage of development and, so far, have provided relatively little in the way of an extension of available diagnostic information. Sometimes the methods provide extensions to existing techniques, for example by the detection of bcr rearrangements in patients who have CML or ALL but do not have a detectable Philadelphia chromosome. Another example is retrospective diagnosis of gene rearrangements using DNA from slide preparations. However, it should be noted that it has only very recently been shown that there is likely to be a causal relationship between the Ph chromosome and leukaemia. Daley et al (1990) induced CML in mice by bone marrow transplantation of cells infected with a retrovirus encoding P210bcr/abl and Heisterkamp et al (1990) produced mice transgenic for a BCR/ABL P190 DNA construct and showed that the progeny died of acute leukaemia (mostly ALL). We have not summarized studies of the incidence of activated oncogenes such as RAS in leukaemia and myelodysplasia. Such oncogenes appear to be involved in many tumours and may well indicate either a predisposition to cancer or a particular stage of malignancy, but their analysis does not at present help in making a diagnosis. It is likely that, as we understand more about the nature of the malignant process, we shall be able to use genetic techniques to enhance considerably both diagnostic and prognostic precision.
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PMID:Molecular biology and leukaemia diagnosis. 227 97

We used a modification of the polymerase chain reaction (PCR) to amplify the specific bcr-abl mRNA from 14 patients with chronic myeloid leukemia (CML) who had previously received non T cell depleted allogenic bone marrow transplantation (BMT). Two types of reactions were used: a single step amplification with 5' and 3' primers, and a double step PCR in which products of the first amplification were reamplified using nested primers. The latter procedure was highly sensitive and capable of detecting one abnormal cell in 10(7) cells. At the time of PCR analysis, all 14 patients were in hematological remission, and 13 were in cytogenetic remission. PCR analysis revealed rearranged bcr-abl mRNA in five patients. The interval from transplant in those five patients ranged from 3 to 63 months. Two of the five positive patients were reexamined after 3 months and were found negative by double step PCR. Our findings suggest that after non-T cell depleted BMT the eradication of the leukemic clone probably occurs in some patients. Other patients, however, proved to have a small number of abnormal cells even at long intervals after BMT, although these cells could only be detected transiently in some patients. The significance of these abnormal cells with respect to the risk of leukemic relapse remains to be determined.
Leukemia 1990 Jan
PMID:Detection of minimal residual disease in chronic myeloid leukemia patients after bone marrow transplantation by polymerase chain reaction. 229


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