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

The Philadelphia (Ph) translocation is responsible for the generation of the chimeric BCR/ABL oncogene. The Ph chromosome constitutes the earliest detectable chromosome abnormality in chronic myelogenous leukemia and is also found in acute lymphoblastic leukemia. Mice transgenic for a P190 BCR/ABL-producing DNA construct develop lymphoblastic leukemia/lymphoma and provide an opportunity to study early stages of the disease as well as progression. In this study, we have karyotyped the bone marrow of 10 19-day-old BCR/ABL P190 transgenic mice from a line that reproducibly develops leukemia/lymphoma. Leukemic cells from 17 terminally ill transgenic founders and progeny were also karyotyped as well as bone marrow transplant recipients of leukemic donor marrow. Karyotypically visible aberrations were absent from the early stages of BCR/ABL P190-generated leukemia and normal metaphases could be found even in the terminal stages of the disease. A high frequency of aneuploidy was found in advanced leukemia, with a marked preference for the gain of mouse chromosomes 12, 14, or 17. These results point to a primary role for BCR/ABL in leukemogenesis and suggest a destabilizing effect of the BCR/ABL gene on the regulation of cell division.
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PMID:Clonal development and karyotype evolution during leukemogenesis of BCR/ABL transgenic mice. 173 87

Philadelphia-chromosome positive chronic myeloid leukemia cells in chronic phase (CML-CP) or blast crisis (CML-BC) and normal bone marrow cells (NBMC) were incubated in vitro with antisense oligonucleotide specific against the BCR/ABL breakpoint junction to examine the possibility of selective inhibition of leukemia growth. Growth capability was determined in vitro by colony assay in semisolid medium in the presence of interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF). The 18-mer antisense directed against the specific BCR/ABL mRNA breakpoint region diminished the colony formation by CML-CP and CML-BC cells, but not by NBMC. Scrambled oligomer did not affect significantly the growth of leukemic and normal cells. If CML-BC cells were mixed with NMBC and incubated with specific BCR/ABL antisense oligomer, leukemic colonies were selectively inhibited, as was shown by reverse, transcriptase-polymerase chain reaction (RT-PCR) performed to detect BCR/ABL mRNA in single colonies. These results confirm the possibility of selective inhibition of leukemia cells by antisense treatment.
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PMID:Gene-targeted specific inhibition of chronic myeloid leukemia cell growth by BCR-ABL antisense oligodeoxynucleotides. 179 39

The polymerase chain reaction (PCR) is a novel technique for the in vitro amplification of specific short DNA fragments, which permits a selective and up to 10(7) fold enrichment of the target sequence. The method is increasingly being used for the molecular genetic analysis of hereditary, infectious and neoplastic disorders. The use of PCR for the detection of minimal residual disease in particular types of leukaemia or lymphoma, such as chronic myelogenous leukaemia expressing specific BCR/ABL-RNA and follicular non-Hodgkin lymphoma with the chromosomal translocation t(14;18) are reviewed. In acute lymphoblastic leukaemia clone-specific sequences from rearranged antigen receptor genes may be molecular markers suitable for amplification. Although PCR holds great promise for "molecular" staging and follow-up, several technical problems have to be kept in mind, and the clinical relevance of PCR-based evidence of minimal residual disease in haematological malignancies requires further investigation.
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PMID:The polymerase chain reaction: a new tool for the detection of minimal residual disease in haematological malignancies. 182 49

A leukemia line KOPN30bi was established from a patient of acute lymphoblastic leukemia with Philadelphia chromosome. The clonal rearrangement of the immunoglobulin heavy chain gene was identical between KOPN30bi and the predominant clone in the fresh sample (S1) from which KOPN30bi was established, indicating that they are of the same clonal origin. The study of the T cell receptor (TCR) genes including TCR beta, gamma, delta loci showed none of these loci was identical between KOPN30bi and S1. The result of the TCR delta region analysis which was rearranged on one of the alleles in KOPN30bi and was deleted on both alleles in S1, however, indicated KOPN30bi was not a derivative of S1. Polymerase chain reaction, using oligonucleotide probe corresponding to the N region sequence of V gamma-J gamma juncture of KOPN30bi, indicated that only one % of the blast cells in S1 corresponded to KOPN30bi. These studies indicated that the predominant clone in the fresh sample, although it occupied more than 99% of the blasts, did not represent the characteristics of the target cell for leukemogenesis, and furthermore that the leukemogenic molecular mechanisms such as P190 type BCR/ABL translocation are not enough to freeze the differentiation of the target cell.
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PMID:[Antigen receptor gene analysis in lymphoid malignancies--a study using the polymerase chain reaction]. 189 Jul 40

A modified two-step polymerase chain reaction (PCR) was used for the amplification of BCR/ABL mRNA in 16 patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) following allogeneic bone marrow transplantation (BMT). At different intervals after BMT, patient cells were assessed for the presence of BCR/ABL mRNA by two subsequent rounds of PCR amplification; this procedure increased the sensitivity for the detection of one Ph+ cell in 10(4-5) to one cell in 10(5-6). Eight of 16 patients were negative by two-step PCR 1-39 months after BMT, suggesting an elimination of Ph-positive cells or a decrease below the threshold of detection. Although five patients showed negative results by the one-step PCR only, they were tested positive when nested primers were used, indicating a substantial decrease in the amount of BCR/ABL target mRNA compared with earlier pre- or post-transplant analyses. One patient who was still PCR positive 27 months after BMT became negative 12 months later. Persistence of BCR/ABL mRNA-expressing cells correlated with subsequent clinical relapse only when the transplantation was performed during blast crisis. All patients who underwent transplantation in chronic phase, including those with BCR rearrangement by PCR, are in clinical and hematological remission between 24 and 95 months after BMT. We conclude that aggressive chemotherapy combined with total body irradiation is unable to completely eradicate the malignant clone in all CML patients, and it might be speculated that other mechanisms (e.g., graft versus host reaction [GVHD] or graft versus leukemia effect [GVL]) may effectively eliminate residual leukemic cells.
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PMID:Apparent decrease and elimination of BCR/ABL mRNA-expressing residual cells in patients with chronic myelogenous leukemia after allogeneic bone marrow transplantation. 193 96

We investigated the effects of brief (2 h) and continuous exposure to recombinant interferon-alpha (2a) (rIFN-alpha) on the proliferation of primitive (blast colony-forming cells, Bl-CFC) and committed myeloid progenitor cells (BFU-E and GM-CFC) derived from blood and bone marrow of patients with chronic myeloid leukaemia (CML) and normal subjects. In all three clonogenic assays, rIFN-alpha suppressed colony formation in a dose-dependent manner. No differences were detected in the proliferation of CML or normal Bl-CFC and GM-CFC exposed to rIFN-alpha. Erythroid colony formation by normal, but not by CML BFU-E, was inhibited by relatively low concentrations (100 U/ml) of rIFN-alpha. However, in patients whose blood or marrow contained a mixture of Philadelphia chromosome (Ph)-positive and Ph-negative BFU-E, cytogenetic analysis of individual erythroid colonies showed no differential inhibition by rIFN-alpha. We found no difference in the sensitivity to rIFN-alpha of GM-CFC from patients whose leukaemic cells expressed BCR/ABL mRNA with the b2a2 junction and that of GM-CFC from patients with the b3a2 mRNA. We conclude that (1) rIFN-alpha does not have a significant leukaemia-specific effect on the progenitor cells detected in these assays, and (2) the sensitivity of CML GM-CFC to rIFN-alpha is independent of the type of BCR/ABL message present in the cells. The clinical efficacy of rIFN-alpha could be due to selective toxicity to cells not assayed in this study, to effects on accessory cells or to alterations induced in progenitor cell/stromal cell interactions.
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PMID:The effects of interferon-alpha on the proliferation of CML progenitor cells in vitro are not related to the precise position of the M-BCR breakpoint. 200 17

Philadelphia positive multiple myeloma is a very rare event and, so far, no molecular data about the involvement of the BCR and C-ABL genes are available. We report here the case of a 64-year-old woman presenting with a typical multiple myeloma and a complex Philadelphia (Ph) chromosome that we investigated at a molecular level using conventional DNA techniques and the polymerase chain reaction (PCR). No rearrangement was observed within the major breakpoint cluster region (M-BCR) although she was found to have a P190 BCR/ABL hybrid transcript using PCR. As far as we know, this is the first description of a P190-type mRNA in a patient with a chronic lymphoid disorder. Since P190 is almost always associated in man with acute forms of hematological malignancies, this suggests that other factors may play a role in determining the phenotype of the disease.
Leukemia 1990 Nov
PMID:P190 BCR/ABL transcript in a case of Philadelphia-positive multiple myeloma. 223 86

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

The BCR/ABL gene, formed by the Philadelphia chromosome translocation (Ph1) of human chronic myelogenous leukemia, encodes an altered ABL gene product, P210. P210 is strongly implicated in the malignant process of chronic myelogenous leukemia, but it precise role is unknown. Infection of long-term bone marrow cultures enriched for B-lymphoid cell types with a Moloney murine leukemia virus retroviral vector containing the BCR/ABL cDNA resulted in clonal outgrowths of immature B-lymphoid cells which expressed abundant P210 kinase activity. Surprisingly, infection of long-term myeloid lineage-enriched cultures also resulted in clonal outgrowths of immature B-lymphoid cells. The P210-expressing lymphoid cell lines resulting from either type of culture were resistant to the lethal effects of corticosteroids. These findings indicate that high levels of P210 expressed from a Moloney murine leukemia virus long terminal repeat preferentially stimulate the growth of immature B-lineage cells, and this effect is apparent even in myeloid lineage-enriched cultures, in which few if any lymphoid cells can be detected prior to infection.
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PMID:Selective transformation of primitive lymphoid cells by the BCR/ABL oncogene expressed in long-term lymphoid or myeloid cultures. 326 66


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