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)

The polymerase chain reaction (PCR) has become a standard method for highly sensitive detection of the bcr/abl rearrangement in patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). The exquisite sensitivity of the PCR facilitates the detection of residual leukemic cells after chemotherapy or after bone marrow transplantation. However, the detection of minimal residual disease does not yield any information on the malignant potential of the bcr/abl-rearranged cells. Qualitative PCR is therefore of limited prognostic value in the monitoring of residual leukemia. We have adapted the PCR for quantitative evaluation of cells carrying the bcr/abl rearrangement and by means of two exemplary cases of CML patients after bone marrow transplantation and under treatment with alpha-interferon, respectively, we show that this new technique is suitable for the long term follow-up of the activity of the residual bcr/abl rearranged clone. Longitudinal monitoring of residual disease by the technique presented provides a novel tool for detection of incipient relapse at a very early stage.
Leukemia 1992 Jun
PMID:Monitoring of residual disease in chronic myelogenous leukemia by quantitative polymerase chain reaction. 160 87

Herbimycin A, a benzoquinonoid ansamycin antibiotic, reduces intracellular phosphorylation by some tyrosine kinases, including v-abl. The mouse megakaryoblastic cell line C1 expresses v-abl protein at high levels. Herbimycin A at about 20 ng/ml caused 50% inhibition of growth of C1 cells but at 100 ng/ml scarcely affected the growth of another mouse leukemia cell line, M1 cells, or of normal bone marrow cells. Injection of 10(6) C1 cells into nude mice resulted in death of all the mice within 30 days. Administration of herbimycin A significantly enhanced the survival of mice inoculated with C1 cells but scarcely affected the survival of mice inoculated with M1 cells. These results suggest that herbimycin A and/or related compounds may be useful for treatment of some types of leukemia in which tyrosine kinase activity is implicated as a determinant of the oncogenic state.
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PMID:Herbimycin A, an inhibitor of tyrosine kinase, prolongs survival of mice inoculated with myeloid leukemia C1 cells with high expression of v-abl tyrosine kinase. 161 78

In Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL), some cytogenetic studies have suggested clonal derivation from a multipotential stem cell. The role of the product of the chimeric gene, P190, is not, however, well understood. We examined the expression of P190-type bcr/abl in single hematopoietic colonies obtained at various clinical stages of a patient with Ph1-positive ALL, using the polymerase chain reaction (PCR). Seven out of 58 colonies examined expressed P190-type bcr/abl. Five out of seven colonies were granulocyte/macrophage (GM) colonies and two were erythroid colonies. The cell lineages of these colonies were confirmed by testing for the expressions of the myeloperoxidase (MPO) gene in the GM colonies and the beta-globin gene in the erythroid colonies. These results suggest transformation of multipotential stem cell in this patient and confirm that expression of the P190-type bcr/abl fusion gene permits stem cell differentiation leading to Ph1-positive ALL.
Leukemia 1992 Aug
PMID:P190-type bcr/abl expressed in myeloid colonies in a patient with Ph1-positive acute lymphoblastic leukemia. 164 Jul 30

Abelson murine leukemia virus is an acutely transforming replication-defective virus which encodes a transforming protein with tyrosine-specific protein kinase activity. A variety of benzopyranone and benzothiopyranone derivatives have been identified which selectively inhibit the v-abl tyrosine protein kinase with 50% inhibitory concentrations ranging from 1 to 30 microM. The most active derivative inhibited v-abl with a Ki value of 0.9 microM. Active derivatives showed selectivity for the v-abl tyrosine protein kinase relative to the epidermal growth factor receptor tyrosine protein kinase (50% inhibitory concentration greater than 100 microM). Protein kinase C and protein kinase A, two members of the serine/threonine protein kinase family, were not inhibited by benzopyranones or benzothiopyranones (50% inhibitory concentration greater than 100 microM). Kinetically, a representative derivative (compound 2) showed competitivity with respect to ATP and noncompetitive behavior with respect to the exogenous peptide substrate. Autophosphorylation of p120v-abl and recombinant p70v-abl tyrosine protein kinases were also inhibited by benzopyranones and benzothiopyranones in vitro. When tested in Abelson murine leukemia virus-transformed BALB/c cell, active benzopyranone and benzothiopyranone derivatives inhibited tyrosine phosphorylation of cellular proteins by the v-abl tyrosine protein kinase.
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PMID:Benzopyranones and benzothiopyranones: a class of tyrosine protein kinase inhibitors with selectivity for the v-abl kinase. 164 41

Mouse C1 line cells are megakaryoblastic cells established by coinfection of Abelson murine leukemia virus and recombinant simian virus 40. We examined the effects of various compounds on growth and differentiation of these cells. Megakaryocytic differentiation of C1 cells was not induced by cytokines that stimulate megakaryocytic maturation of normal progenitor cells, such as interleukin 3 and 6 and granulocyte-macrophage colony-stimulating factor. However, the cells were induced to differentiate into megakaryocytes by treatment with some protein kinase inhibitors. The inhibition of v-abl tyrosine kinase activity preceded induction of differentiation of the cells treated with tyrosine kinase inhibitors such as genistein, herbimycin A, and erbstatin. Treatment of C1 cells with a v-abl antisense oligomer inhibited their proliferation and induced acetylcholinesterase activity, a typical marker of megakaryocytic differentiation. These results suggest that inhibition of v-abl function is associated with induction of megakaryocytic differentiation of C1 cells. Among the compounds tested, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a potent inhibitor of cyclic nucleotide-dependent and Ca(2+)-phospholipid-dependent (protein kinase C) protein kinases, was the most potent inducer of differentiation of C1 cells. However, the differentiation-inducing effect of H-7 was unlikely to be mediated through inhibition of protein kinase C or cyclic nucleotide-dependent kinases, because other types of inhibitors of these kinases were not effective, and a protein kinase activator (phorbol ester) induced differentiation of C1 cells. Moreover, neither v-abl mRNA expression nor v-abl kinase activity in C1 cells was affected by treatment with H-7. These findings indicate that induction of megakaryocytic differentiation by H-7 is not related to inhibition of v-abl kinase, but rather to some novel function of H-7.
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PMID:Induction by some protein kinase inhibitors of differentiation of a mouse megakaryoblastic cell line established by coinfection with Abelson murine leukemia virus and recombinant SV40 retrovirus. 165 10

We recently showed that hemopoietic stem cells expressing the v-abl oncogene can cause leukemia when injected into lethally irradiated recipient mice. Progenitor cells expressing v-abl did not significantly contribute to disease development, and the leukemia was monoclonal in origin. By serially transplanting v-abl-transduced hemopoietic stem cells into normal, nonirradiated syngeneic recipients, we showed that multiple stem-cell clones do exist in some recipients. These cells fluctuated as normal stem cells do and could home to normal bone marrow. Based on the time course of disease, the recipients developed either an acute or a chronic phase of disorder. All recipients with the acute disease had stem-cell clones with random Abelson murine leukemia virus integration sites. All recipients with the chronic disorder had a specific Abelson murine leukemia virus integration site. We believe this abl-specific integration site, termed ASI, is important in abl-mediated stem-cell leukemogenesis.
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PMID:Chronic myeloproliferative disease induced by site-specific integration of Abelson murine leukemia virus-infected hemopoietic stem cells. 168 23

The effect of two missense mutations in abl on transformation by Abelson murine leukemia virus was evaluated. These mutations led to the substitution of a histidine for Tyr-590 and a glycine for Lys-536. Both changes gave rise to strains that were temperature dependent for transformation of both NIH 3T3 cells and lymphoid cells when expressed in the context of a truncated Abelson protein. In the context of the prototype P120 v-abl protein, the Gly-536 substitution generated a host range mutant that induced conditional transformation in lymphoid cells but had only a subtle effect on NIH 3T3 cells. The combination of both substitutions gave rise to a P120 strain that was temperature sensitive for both NIH 3T3 and lymphoid cell transformation. The Abelson proteins encoded by the temperature-sensitive strain displayed in vitro kinase activities that were reduced when compared with those of wild-type proteins. In vivo, levels of phosphotyrosine were reduced only at the restrictive temperature. Analysis of cells expressing either the wild-type P160 v-abl protein or the P210 bcr/abl protein and an Abelson protein encoded by a temperature-sensitive strain failed to correct this defect, suggesting either that tyrosine phosphorylation in vivo is an intramolecular reaction or that the protein encoded by the temperature-sensitive strain is a poor substrate for tyrosine phosphorylation in vivo. These results raise the possibility that tyrosine phosphorylation of Abelson protein plays a role in transformation.
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PMID:Temperature-sensitive mutants of Abelson murine leukemia virus deficient in protein tyrosine kinase activity. 169 37

Transformed Fisher rat fibroblast cell lines by Abelson murine leukemia virus frequently revert to the normal phenotype in usual culture conditions. Molecular biological analysis of three revertant clones isolated from the transformants showed that their morphological reversions were due to inactivation of the v-abl oncogene at multiple steps including transcription, translation or v-abl protein kinase activity itself without any change in structural gene expression of helper virus. These findings suggest the existence of a specific mechanism(s) for elimination of the v-abl oncogene by segregation, mutation, or gene rearrangement in these cells.
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PMID:Characterization of flat revertants isolated from cells transformed by Abelson murine leukemia virus (Ab-MuLV). 170 65

The cellular gene c-abl is the normal homologue of the transforming gene (v-abl) within the genome of the Abelson leukaemia virus. The cDNA sequence coding for the cellular form of the murine abl gene (c-abl type IV) has been inserted into the baculovirus transfer vector, pAc36C, so that the c-abl gene is under the control of the polyhedrin promoter of Autographa californica nuclear polyhedrosis virus (AcNPV). Spodoptera frugiperda cells infected with the recombinant transfer vector in the presence of wild type AcNPV DNA yielded recombinant, polyhedrin negative virus that expressed moderate levels of the c-Abl protein (representing approx. 0.5-1% of the stained cellular proteins as determined by densitometric scanning). The insect derived c-Abl protein was compared to the P210-BCR/ABL protein from K562 cells, a cell line derived from a patient with chronic myelogenous leukaemia. Antibodies raised against synthetic peptides based on c-abl encoded peptides react with the insect derived c-Abl. In addition, the baculovirus derived c-Abl protein has a tyrosine kinase activity as demonstrated by phosphorylation of a synthetic polypeptide and also by autophosphorylation. Phosphoamino acid analysis of immunoprecipitated, autophosphorylated baculovirus derived c-Abl protein indicates that the majority of label incorporated is on the tyrosine residues. Immunofluorescence microscopy has been used to show that the majority of the c-Abl protein expressed in cells infected with recombinant virus is located in the nuclear and plasma membranes.
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PMID:Expression of the mouse c-abl type IV proto-oncogene product in the insect cell baculovirus system. 173 71

We have utilized the polymerase chain reaction (PCR) to sensitively detect persistence of the chronic myelogenous leukemia (CML) malignant clone and to study bcr/abl mRNA splicing patterns following bone marrow transplantation. Thirteen of sixteen patients displayed persistent malignant cells during post-BMT clinical remission. In two patients bcr/abl mRNA was detected 4 and 9 months prior to clinical relapse. In eleven of fourteen patients in continued clinical remission malignant cells were detected post-BMT. Ten of these eleven patients were also cytogenetically normal. Seven patients have lost all evidence of bcr/abl transcript, but only at 1-2 years posttransplant, while four have shown persistence of the bcr/abl transcript from 28 days to 3 years post-BMT and one has converted from an initially negative result at 1 year post-BMT to detectable levels of chimeric mRNA at 2 years. Thus, 8/9 patients tested at or before 6 months, 7/12 at 1 year, and 3/10 at 2 years showed persistent detectable CML cells. Intriguingly, mRNA splicing patterns changed in 5 patients following BMT, with complete loss of mRNA containing bcr exon 3 (n = 2) or new appearance of mRNA not containing bcr exon 3 (n = 2). A single patient transiently lost evidence of bcr exon 3 expression while persistently expressing the bcr exon 2/abl exon 2 splice. Our data suggest that the majority of patients harbor small numbers of malignant cells following transplantation, and that such persistence may not inevitably predict clinical relapse. Complete elimination of the malignant CML clone post-BMT may rely on immunological mechanisms (e.g., graft-vs-leukemia).
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PMID:bcr/abl mRNA detection following bone marrow transplantation for chronic myelogenous leukemia. 175 65


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