Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cure of leukemia by allogeneic BMT is achieved by the combined effect of the myeloablative preparative regimen and an allo-immune response of donor cells to residual leukemia termed the graft-versus-leukemia (GVL) effect. In the first year following BMT for CML, PCR used to detect the leukemia-specific BCR/ABL message frequently reveals subclinical levels of persisting leukemia. In a meta-analysis of reports on qualitative PCR findings after BMT for CML in 12 recently published series, we found that for unmanipulated BMT in chronic phase, PCR detection was not associated with a higher relapse risk and that most patients became PCR negative within 2 years post-BMT. In contrast, PCR detection of BCR/ABL transcripts was a more reliable predictor in recipients of T cell-depleted BMT and in those transplanted in accelerated or blastic phase of their disease. For accurate prediction of relapse, serial quantitative PCR is necessary. It could also be used to monitor efficacy of experimental treatments of relapse with interferon or donor lymphocyte transfusions. Furthermore, studies of the association of GVHD with PCR detection of BCR/ABL message may shed light on the relationship of GVL with minimal residual disease in CML.
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PMID:Minimal residual disease after bone marrow transplantation for chronic myelogenous leukemia and implications for graft-versus-leukemia effect: a review of recent results. 799 33

Previous studies designed to identify the Ph chromosome in T lymphocytes from patients with chronic myelogenous leukaemia (CML) were mostly based on small numbers of patients. To examine the possibility that the occasional CML patient might have major penetration of the T-cell compartment by the leukaemic clone, we studied interphase T cells from the blood of 11 CML patients conventionally treated in chronic phase and three in relapse after allogeneic bone marrow transplant (BMT) by fluorescence in situ hybridization using BCR and ABL cosmid probes. Granulocytes from the same patient and cells from the SD-1 CML cell line served as positive controls. Cells with juxtaposition of BCR and ABL signals or with the two signals up to one signal diameter apart were scored as positive. In each CML patient the incidence of 'positive' T cells was much less than in positive controls and similar to that found in negative controls (mean values +/- 1 SD: 7.7 +/- 3.6; 91.2 +/- 3.1, and 5.6 +/- 2.2, respectively). We conclude that none of the patients studied by this technique had any appreciable proportion of BCR/ABL-positive T cells in the circulation.
Leukemia 1994 Jul
PMID:T lymphocytes in chronic myelogenous leukaemia (CML): no evidence of the BCR/ABL fusion gene detected by fluorescence in situ hybridization in 14 patients. 803 12

BCR/ABL tyrosine kinases are encoded by hybrid oncogene bcr/abl which is a result of t(9;22) reciprocal translocation. Bcr/abl oncogene is located on Philadelphia chromosome which is detectable in hematopoietic cells of more than 95% of patients with chronic myelogenous leukemia, and in some cases of acute lymphocytic leukemia (20-35%) and acute myeloblastic leukemia (5%). Because BCR/ABL tyrosine kinase is localized in the cytoplasm, cooperation with other cytoplasmic and nuclear molecules is necessary for the induction of leukemia. Identification of the molecular mechanisms involved in transduction of the oncogenic signal is likely to be useful in elucidating the molecular mechanisms of leukemogenesis and may eventually lead to the identification of novel targets for antileukemia therapy. One of the possible treatment--inhibition of bcr/abl oncogene expression by antisense strategy--is described below.
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PMID:[Molecular basis of chronic granulocytic leukemia: from test-tube to patient]. 806 3

We have investigated the involvement of tumor suppressor genes (p53 and RB1) and dominantly acting oncogenes (Ras family genes) in BCR/ABL positive and negative chronic myeloproliferative disorders (CMPD) at different stages of the disease, including 26 cases of BCR/ABL+ chronic myeloid leukemia (CML) blast crisis, 9 myelosclerosis with myeloid metaplasia, 4 polycythemia vera, 10 essential thrombocythemia, 1 juvenile CML, and 8 BCR/ABL- CML. The presence of mutations in p53 exons 5 through 9, as well as in RB1 exons 10-27 and in N-, K-, H-Ras exons 1 and 2 was tested by the PCR-Single Strand Conformation Polymorphism technique and by PCR-Direct Sequencing. In addition, Southern blot analysis was used to investigate the occurrence of gross rearrangements in the p53 gene as well as loss of heterozygosity at 17p13, the site of p53. Acute phase BCR/ABL-CMPD cases displayed a high frequency of p53 (2/7) and Ras (3/7) lesions, whereas BCR/ABL- CMPD in chronic phase displayed only germline p53 and Ras sequences. Conversely, p53 inactivation was restricted to only 1/26 cases of BCR/ABL+ CML blast crisis. No alterations in the RB1 gene were detected in any of the cases analyzed. These data indicate that p53 inactivation and/or Ras activation might play a role in acute transformation of BCR/ABL- CMPD and that the molecular mechanisms of tumor progression may be different in BCR/ABL+ versus BCR/ABL-CMPD.
Leukemia 1994 Apr
PMID:Molecular mechanisms of tumor progression in chronic myeloproliferative disorders. 815

Chronic myelogenous leukemia (CML) is associated with a translocation of the BCR and the ABL genes, t(9;22). Results of this event are transcription and translation products that are unique to malignant cells. We therefore designed synthetic ribozymes which are capable of exclusively cleaving the BCR/ABL B3A2-type mRNA without altering normal cellular transcripts. Synthetic B3A2-type transcripts could only be cleaved by B3A2-type mRNA targeted ribozymes and not by any of the controls. The B3A2-type mRNA directed ribozyme, on the other hand, did not cleave any of the control transcripts. The effective delivery of ribonucleic acids by lipofection into K562 cells could be demonstrated by fluorescent microscopy, slot blot analysis, and RNA polyacrylamide gel electrophoresis. In vivo, we were able to induce a significant inhibition of the proliferation of K562 cells with ribozymes directed against the B3A2-type mRNA. Quantitative PCR analyses showed an up to fivefold reduction of the relative number of BCR/ABL mRNA molecules per single cell after exposure to ribozymes compared to controls. We conclude that ribozymes targeted against the B3A2-type BCR/ABL mRNA function in vitro and in vivo.
Leukemia 1993 Nov
PMID:In vitro and in vivo effects of synthetic ribozymes targeted against BCR/ABL mRNA. 823 Dec 47

The presence of the BCR/ABL chimeric gene is the hallmark of defined types of human leukemia. To increase our knowledge of the oncogenic processes and to develop a model for this type of leukemia we generated a BCR/ABL (P190) transgenic mouse line. Over 95% of mice of this line die of leukemia or leukemia/lymphoma within 35-200 days of age. Karyotypically visible genetic alterations were absent from the early stages of BCR/ABL generated leukemia. A high frequency of aneuploidy was found in advanced leukemia indicating a primary and pivotal role for BCR/ABL in leukemogenesis. Moreover, the data suggest that BCR/ABL has a destabilizing effect on the regulation of the cell cycle. BCR/ABL expression was also found in tissues other than hematopoietic cells. However, this did not result in the development of solid tumors, strongly suggesting that the oncogenicity of BCR/ABL is limited to the hematopoietic lineage.
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PMID:Ph-positive leukemia: a transgenic mouse model. 825 94

Leukaemia-specific proteins may be recognized by T-lymphocytes as neoantigens if peptides corresponding to mutated sequences bind to major histocompatibility complex (MHC) molecules on leukaemic cells. We studied the ability of a series of synthetic peptides corresponding to the junctional sequences of BCR/ABL proteins to bind to class I molecules in two human cell lines, LBL 721.174 (T2) (HLA-A2, B5) and BM36.1 (HLA-A1, B35), and one murine cell line RMA-S (H-2Kb, Db). These cell lines are defective in intracellular peptide loading of class I molecules, resulting in markedly reduced cell surface class I expression: class I expression can be rescued by provision of peptides binding to the alleles expressed by the mutant cell. Eighteen peptides spanning the junctional sequences of the b2a2 and b3a2 proteins were tested for their ability to rescue expression of the class I alleles borne by these cells using flow cytometry. Allele-specific control peptides known to bind HLA-A2, HLA-B35, H-2Kb and H-2Db increased expression of these alleles 2- to 3-fold: 0/18 BCR/ABL peptides enhanced HLA-A2, HLA-B35 or H-2Kb expression, but three b2a2 peptides consistently increased H-2Db expression. These results suggest that BCR/ABL junctional peptides are unlikely to be presented to T-cells in association with HLA-A2, HLA-B35 or H-2Kb. Conversely, the finding that some b2a2 peptides bind specifically to H-2Db suggests that a murine model of graft-versus-leukaemia (GVL) could be constructed.
Leukemia 1994 Jan
PMID:Binding of BCR/ABL junctional peptides to major histocompatibility complex (MHC) class I molecules: studies in antigen-processing defective cell lines. 828 83

We have investigated the involvement of the p53 tumor suppressor gene and RAS family proto-oncogenes in BCR/ABL-negative chronic myeloproliferative disorders (CMPD), including nine cases of myelosclerosis with myeloid metaplasia, four polycythemia vera, 10 essential thrombocythemia, one juvenile chronic myeloid leukemia, and eight BCR/ABL-negative chronic myeloid leukemia. Twenty-five samples were studied in the chronic phase, while seven samples were analyzed in the acute accelerated or blastic phase. The presence of mutations in p53 exons 5-9, as well as in N-, K-, H-Ras exons 1 and 2 (containing codons 12, 13, and 61) was tested by the polymerase chain reaction (PCR) single strand conformation polymorphism technique and by PCR direct sequencing. In addition, restriction analysis was performed to screen for gross rearrangements within the p53 locus. Alterations of the p53 tumor suppressor gene and Ras family proto-oncogenes were detected in 2/7 and 3/7 cases of acute phase BCR/ABL-negative CMPD, respectively, while consistently negative in all the chronic phase samples analyzed. These results suggest that p53 inactivation and/or Ras activation might play a role in acute transformation of BCR/ABL-negative CMPD.
Leukemia 1993 Jul
PMID:Mutations in the P53 and RAS family genes are associated with tumor progression of BCR/ABL negative chronic myeloproliferative disorders. 832 Oct 46

The very rapid development in the last few years of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma now offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is presumably achieved when the DNA sequences amplified are truly leukaemia-specific, such as BCR/ABL in chronic myelogenous leukemia, RARA PML/RARA in t(15;17) acute myelogenous leukemia, DEK/CAN in t(6;9) AML, PBX1/E2A in t(1;19) acute lymphoblastic leukemia (ALL), or TAL-1 deletions in other T-ALLs. Comparable sensitivity may be achieved by using immunoglobulin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. However, the presence of similar sequences in IgH genes from normal B lymphocytes may decrease the specificity. For clinical purposes the crucial issues are the following. Can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained in remission provide information about the probability of cure or of relapse? Can techniques be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues were addressed at the 4th Workshop of the Molecular Biology/BMT Study Group that took place in Bristol UK on 9-10 May 1992.
Leukemia 1993 Aug
PMID:Molecular evidence of minimal residual disease after treatment for leukaemia and lymphoma: an updated meeting report and review. 835 Jun 33

We describe a BCR/ABL rearrangement positive but Philadelphia chromosome negative status in a 9-year-old boy suffering from an acute myelogenous leukaemia (AML). This case was detected in a prospective PCR screening procedure including 21 children with newly diagnosed AML and 150 children with acute lymphoblastic leukaemia (ALL). We found a 5.4% incidence of BCR/ABL rearrangement positive cases in pre-B and c-ALL in childhood.
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PMID:BCR-ABL rearrangement in a child with acute myelogenous leukaemia without a Philadelphia chromosome. 839 40


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