Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe the polymerase chain reaction (PCR) method using stained bone marrow smears as sources of RNA. The amount of extractable RNA decreased during the process of making and staining bone marrow smears. The sensitivity of the reverse transcriptase-based polymerase chain reaction (RT-PCR) method for detecting target mRNA-positive cells in 5 x 10(5) suspended cells and stained bone marrow smears were 1:10(5) and 1:5000, when we used K562 cells. The bone marrow smears of 21 patients with chronic myelogenous leukemia (CML) were examined using this method. We extracted RNA from stained specimens stored at room temperature for 5-14 years. Twelve of 21 (57%) smears showed positive results for bcr/abl. The carrier RNA improved the recovery when added at the step of RNA extraction. These data indicate that mRNA is present in stained bone marrow smears for at least 14 years and that the sensitivity of RT-PCR is adequate for molecular analysis.
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PMID:Detection of bcr/abl mRNA in stained bone marrow smears. 788 52

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

Many patients with chronic myeloid leukemia (CML) retain a certain degree of normal hematopoiesis at disease presentation. This fact, suspected on the basis of cytogenetic findings, has been confirmed by long-term bone marrow cultures (LTBMC) and the combined use of phenotypic and molecular studies. Based on the lack of HLA-DR expression, it has been possible to recognize a benign subpopulation within the stem-cell compartment in CML. Different in vitro techniques have been developed for the selection of these benign progenitors, including LTBMC, marrow incubation with cytolytic drugs or interferon, positive selection based on their phenotypic characteristics, and exposure to synthetic antisense oligodeoxynucleotides. In vivo selection with interferon or intensive chemotherapy is also possible. The primary goal of the selection of benign hematopoietic progenitors is their use for autotransplantation. To date, a few hundred CML patients have been submitted to the latter procedure using bone marrow or peripheral blood. The fact that the majority of them show evidence of persistent disease emphasizes the necessity for better selection methods of the benign progenitors, for intensifying the conditioning regimen to reduce the tumor burden as much as possible, and for the use of adjuvant therapy post-transplantation. Future trends include the refinement of positive selection methods, negative selection by taking advantage of the different stromal adhesiveness of the benign and malignant progenitors, or the use of autologous natural killer cells, antisense oligodeoxynucleotides, or specific antibodies to the bcr/abl junction region, and retroviral marking to determine the origin of relapse in autologous transplantation.
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PMID:Benign hematopoietic progenitors in chronic myeloid leukemia: current status and future prospects. 808 13

A 13-year-old boy without any previous illness was diagnosed as suffering from acute lymphoblastic leukemia (ALL). After a period of apparent complete remission until 17 years of age, the presence of Ph1 positive cells in bone marrow was demonstrated by karyotype analysis. This finding suggested chronic myelogenous leukemia (CML) because of the absence of blastic changes in bone marrow but mild leukocytosis with basophilia at that time. Six months later he had a relapse (blast crisis) with the appearance of peroxidase negative lymphoid blasts and myeloid surface markers. To make differential diagnosis, leukemia blasts at onset and relapse were examined for rearrangement of immunoglobulin JH gene and bcr/abl fusion mRNA, and were found to have the same JH gene rearrangement pattern and the same bcr/abl mRNA of bcr exon 2/abl exon 2. These results indicate an unusual case of CML which appeared in blast crisis at onset, followed by a long-term remission.
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PMID:bcr/abl mRNA in leukemic blasts of an unusual patient with acute lymphoblastic leukemia followed after 5-year remission by chronic myelogenous leukemia in blast crisis. 809 37

Highly polymorphic tandemly repetitive DNA sequences provide powerful genetic markers for the identification of individuals by restriction fragment length polymorphisms (RFLP) even in close relatives. Over a three-year period, 61 consecutive patients from a single institution undergoing allogeneic bone marrow transplantation (BMT) for various hematological diseases were grafted with unmanipulated marrow and followed for the development of hematopoietic chimerism. Three synthetic oligonucleotide probes homologous to the so-called minisatellite or variable number of tandem repeat (VNTR) sequences were evaluated in the clinical setting of BMT for their usefulness: (i) to document marrow engraftment or rejection; (ii) to elucidate the kinetics of mixed chimerism; and (iii) in providing a sensitive tool for early detection of relapse. In addition, in patients with CML karyotyping and analysis of bcr/abl gene rearrangement was performed. Using this panel of three oligonucleotide probes, informative markers specific for donor or recipient RFLP could be demonstrated in all cases. Engraftment could be documented in all patients surviving beyond day +14 after BMT. Mixed chimerism was detected in 14% of the patients in the early phase (day +14 to day +78) after BMT but only one patient turned out to become a long-term stable mixed chimera. These results support the hypothesis that lymphocytes of recipient origin surviving the conditioning regimen may considerably contribute to mixed chimerism early after BMT. Long-term stable mixed chimerism is a rare event after BMT with unmanipulated marrow. Simultaneous analysis of chimerism after BMT by VNTR-RFLP, karyotyping, and detection of bcr/abl rearrangement in patients with CML showed corresponding results in nine out of 12 patients. In three patients either one of the methods failed to detect residual recipient cells in the early phase after BMT. Therefore different methods for assessment of mixed chimerism seem to complement rather than to exclude each other. Eleven patients who all exhibited complete chimerism early after BMT relapsed from their underlying disease. In seven of these patients grafted for acute leukemia, analysis of DNA-RFLP had been performed shortly before clinical relapse (30-86 days) and failed to herald relapse. As the sensitivity for the detection of the minor cell population by analysis of DNA-RFLPs is approximately 1%, these data may indicate that relapse of acute leukemia after BMT is characterized by a sudden increase in the percentage of recipient blast cells not detectable even by frequent RFLP analyses.
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PMID:Monitoring of chimerism after allogeneic bone marrow transplantation with unmanipulated marrow by use of DNA polymorphisms. 809

Various lines of evidence suggest that substantial numbers of very primitive normal hematopoietic cells persist in the marrow of most patients with CML, despite the presence of an expanded Philadelphia-Chromosome (Ph) positive population, and that normal clones might, in certain circumstances, have a proliferative advantage over leukemic populations. We have recently demonstrated in 5/8 CML patients with blastic phase (BP) that the blood progenitor cells/(BPC) harvested during early recovery from marrow aplasia were Ph-negative on cytogenetic analysis, suggesting that leukapheresis may provide a useful source of 'normal' progenitors for subsequent reinfusions. We report here an update on 40 patients with Ph + CML and 9 patients with ALL in first or subsequent relapses with associated cytogenetic translocations including t(8;14) t(4;8) t(4;11) and t(9;22). All these patients received intensive conventional chemotherapy and during early recovery from marrow aplasia, when the WBC reached 0.5-2.0 x 10(9)/L, BPC were collected by 4-8 leukapheresis and tested for the persistence of the marker translocations and, when possible, for the presence of the hybrid bcr/abl transcripts by polymerase chain reaction (PCR). In seven out of 10 patients with chronic phase CML, BPC were Ph-negative and in 5 PCR negative. In both accelerated phase patients, BPC were Ph-negative but PCR-positive and in eight out of 28 blastic CML patients, BPC were Ph-negative and in two cases also PCR-negative. Six out of 9 ALL patients, lost the cytogenic translocations. After complete recovery, 16 patients were subsequently given high-dose therapy followed by reinfusion of 'normal' BPC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mobilization of cytogenetically 'normal' blood progenitors cells by intensive conventional chemotherapy for chronic myeloid and acute lymphoblastic leukemia. 810 54

Chronic myelogenous leukemia is caused by a reciprocal chromosomal translocation of human chromosomes 9 and 22. The resulting fusion protein, p210Bcr/Abl, has enhanced tyrosine kinase activity compared with the normal cellular homologue, p145c-Abl. Expression of this chimeric protein in hematopoietic cell lines results in a rapid progression to growth factor independence and increased tyrosine phosphorylation of a number of unidentified cellular proteins. In this study, we show that the phosphorylation state of the hematopoietically restricted tyrosine kinase, p93c-Fes, is increased. Increased phosphorylation of p93c-Fes was detected in p210Bcr/Abl(+) human leukemic cell lines, in primary leukemic cells from patients with chronic myelogenous leukemia, and in myeloid cell lines expressing p210Bcr/Abl after transfection. Furthermore, p93c-Fes phosphorylation was increased by p210Bcr/Abl even when coexpressed in NIH 3T3 fibroblasts. v-abl expression was also found to increase the tyrosine phosphorylation of p93c-Fes. This increased phosphorylation was found to be accompanied by an increase in the ability of p93c-Fes to phosphorylate exogenous substrates. p93c-Fes could contribute to the transforming activity of the abl oncogenes.
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PMID:p210Bcr/Abl and p160v-Abl induce an increase in the tyrosine phosphorylation of p93c-Fes. 811 16

CML is an excellent target for development of selective treatment because of its highly consistent genetic abnormality t(9;22) and unique fusion gene product, p210bcr/abl, although it is not yet clear what form of specific therapy might be effective. Several components of p210bcr/abl are thought to be essential for its transforming activity: These include the constitutive tyrosine kinase activity of abl and the ability of the first exon for bcr both to specifically bind to abl's SH2 binding domain and possibly also to function as a novel type of serine kinase. Relatively little is yet known about what specific abnormalities in the regulatory pathways are caused by the altered tyrosine kinase activity of p210bcr/abl and other bcr/abl oncoproteins, but whatever its precise mode of action proves to be, p210bcr/abl presumably somehow changes the normal pattern of phosphorylation of key regulatory proteins in the signaling pathways so that the genes which normally direct the orderly sequence of proliferation and maturation of the myeloid progenitors are not properly regulated. The end results of this 'disregulation' are that there is asynchronous or discordant maturation; relative to comparable normal progenitors, a higher proportion of CML progenitors exhibit earlier cytoplasmic and delayed nuclear maturation. The leukemic progenitors do not proliferate more rapidly than comparable normal progenitors or have increased ultimate proliferative potential, but they go through one or more additional divisions during passage through the later maturation compartments and also live longer, resulting in overexpansion of the leukemic population. It is important to recognize the close linkage between maturation and proliferation in designing experiments to correlate the molecular and biological abnormalities and in seeking novel therapies to selectively affect the leukemic progenitors.
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PMID:Integration of molecular and biological abnormalities in quest for selective treatment of chronic myelogenous leukemia (CML). 812 37

The in vitro sensitivity of human chronic myeloid leukemia-blast crisis and chronic phase (CML-BC and CML-CP, respectively) cells as well as adherent cell-depleted, T lymphocyte-depleted normal bone marrow cells (A-T-NBMC) to various concentrations of mafosfamide (ASTA Z7654), was examined by colony formation assay in the presence of IL-3 and GM-CSF, to test the possibility of purging of BMC from CML cells. Colony formation by CML cells was inhibited more efficiently than by NBMC. After the incubation with 50 micrograms/ml or 100 micrograms/ml of mafosfamide, the growth of leukemic CFU-GM was totally abrogated in 2/11 or 9/11 cases of CML-BC and in 1/7 or 6/7 cases of CML-CP, respectively. At the same time the CFU-GM arising from normal BMC were not inhibited totally with 50 or 100 micrograms/ml of the drug in any of five experiments. CML cells were still unable to form secondary colonies, while normal BMC were capable of regrowth. The CD34+ cells isolated form CML-BC and CML-CP patients were also more susceptible to mafosfamide cytotoxicity in comparison to CD34+ cells derived from NBMC. To confirm the possibility of purging, CML-BC cells were mixed with NBMC (1:1) and incubated with mafosfamide. Finally, the growing colonies were examined for the presence of bcr/abl hybrid gene by reverse transcriptase-Taq polymerase chain reaction (RT-PCR) and specific hybridization. The bcr/abl gene was not detected in the colonies growing after 100 micrograms/ml, and the signal was diminished after incubation with 50 micrograms/ml of mafosfamide, as compared to control. These results strongly suggest that high concentrations of mafosfamide may be useful for the purging of autologous BMC from CML cells.
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PMID:Successful mafosfamide purging of bone marrow from chronic myelogenous leukemia (CML) cells. 813 96

The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr/abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin A, an inhibitor of tyrosine kinase, preferentially inhibited the growth of Ph1-positive acute lymphoid leukemia (ALL) cell lines, as well as Ph1-positive chronic myeloid leukemia (CML) cell lines. Although noncytotoxic concentrations of herbimycin A induced erythroid differentiation of two CML-derived cell lines, K562 and KU812, in a previous study, the differentiation-inducing effect of herbimycin A on Ph1-positive ALL cell lines was less strong. Herbimycin A enhanced some differentiation-associated properties of one Ph1-positive ALL cell line, L2, but the effect of herbimycin A on the other Ph1-positive ALL cell lines was cytotoxic rather than cytostatic (differentiation-inducing). Several derivatives of herbimycin A were synthesized and their effects on the cell proliferation of Ph1-positive CML and ALL cell lines were examined. The sensitivities of the Ph1-positive cell lines to herbimycin A derivatives were different from the data on the rat kidney cell line infected with Rous sarcoma virus (v-src) derived from a previous study, suggesting bcr/abl kinase may differ in sensitivity from other tyrosine kinases. Moreover, the sensitivities of the ALL cell lines were not the same as those of the CML cell lines. These results suggest that a specific inhibitor of bcr/abl kinase could be an effective antileukemic agent against Ph1-positive CML or ALL.
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PMID:Effects of herbimycin A and its derivatives on growth and differentiation of Ph1-positive acute lymphoid leukemia cell lines. 813 88


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