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 Dutch Childhood Leukemia Study Group (DCLSG) performed a phase III study-Study (ALL) V-to evaluate the effectiveness of rubidomycin in induction therapy with vincristine, prednisone, and L-asparaginase for children (0-15 years) with standard risk acute lymphoblastic leukemia (ALL) (white blood cell [WBC] counts less than 50.10(9)/L, absence of mediastinal mass, and/or cerebromeningeal leukemia). Furthermore, the influence of initial patient and disease characteristics on the outcome was analyzed. Between May 1979 and December 1982, 240 patients entered the study and were randomized into two groups: group A (n = 122) received induction treatment with vincristine (VCR), prednisone (Pred), and L-asparaginase (L-Asp); for group B (n = 118), induction therapy consisted of VCR, Pred, L-Asp, and rubidomycin (Rub). All patients subsequently underwent cranial irradiation (doses adjusted to age) in combination with intrathecal methotrexate; maintenance therapy of 6-mercaptopurine and methotrexate for 5 weeks followed by vincristine and prednisone for 2 weeks was given for 24 months. The complete remission (CR) rate was similar in both groups (94.5%). Event-free survival (EFS) 5 years after diagnosis was higher in group B (62.5 +/- 4.5%) than in group A (54.7 +/- 4.5%), although the difference is not significant (p = 0.20). A high initial WBC (greater than or equal to 10.10(9)/L), age (greater than or equal to 10 years), a low platelet count (less than 100.10(9)/L), and a positive acid phosphatase reaction of the leukemic cells were unfavorable prognostic factors (p less than 0.05). Sex, French-American-British (FAB) classification group, immunophenotype, and treatment in specialized centers did not have a significant impact on event-free survival.
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PMID:Effectiveness of rubidomycin in induction therapy with vincristine, prednisone, and L-asparaginase for standard risk childhood acute lymphocytic leukemia: results of a Dutch phase III study (ALL V). A report on behalf of the Dutch Childhood Leukemia Study Group (DCLSG). 266 46

The physiological role of the colony forming units-spleen (CFU-S) inhibitor Acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) has been studied by observing the effects of AcSDKP deprivation. This deprivation was obtained by injecting polyclonal antiserum directed against AcSDKP into normal untreated mice in order to neutralize the endogenous inhibitor. The dramatic increase in the percentage of CFU-S in DNA synthesis as compared to controls receiving anti-KLH antiserum suggests that AcSDKP plays an important role in the maintenance of CFU-S in physiological quiescent state.
Leukemia 1989 Oct
PMID:The physiological role of the endogenous colony forming units-spleen (CFU-S) inhibitor acetyl-N-Ser-Asp-Lys-Pro (AcSDKP). 277 91

Retrovirus protease is an enzyme that cleaves gag and gag-pol precursor polyproteins into the functional proteins of mature virus particles. The correct processing of precursor polyproteins is necessary for the infectivity of virus particles: in vitro mutagenesis which introduces deletions into the murine leukaemia virus genome produces a protease-defective virus of immature core form and lacking infectivity. A therapeutic drug effective against disease caused by retrovirus proliferation could likewise interfere with virus maturation. The primary structure has so far been determined for the protease of avian myeloblastosis virus, and of murine, feline and bovine leukaemia viruses. Amino acid sequencing of the retrovirus proteases, either after their purification or from prediction from the nucleotide sequence, shows that they possess the Asp-Thr-Gly sequence characteristic of the aspartyl proteinases. In this report we show that retrovirus proteases belong to the aspartyl proteinase group and demonstrate an inhibition by the aspartyl proteinase-specific inhibitor, pepstatin A, on the activity of bovine leukaemia, Moloney murine leukaemia and human T-cell leukaemia virus proteases.
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PMID:Inhibition of retroviral protease activity by an aspartyl proteinase inhibitor. 282 9

The biological activity encoded in the putative protease gene (pro) of human T-cell leukemia virus type I was investigated by using a vaccinia virus expression vector. The 53-kilodalton gag precursor polyprotein was processed into the mature p19, p24, and p15 gag proteins when the gag and protease-coding sequence was expressed under the control of a vaccinia virus promoter, suggesting that the protease may be synthesized through the mechanism of ribosomal frame shifting. The processing defect of a protease mutant could be complemented by cointroduction of a wild-type construct into the cell, demonstrating that the pro gene encodes the biologically active protease molecules which are capable of processing the gag precursor polyprotein in vivo in trans. A study involving the use of a variety of mutants constructed in vitro revealed that the protease consists of a nonessential carboxy-terminal region and a part essential for its activity, including the putative catalytic residue, aspartic acid. Furthermore, a cluster of adenine residues positioned at the overlapping region between the gag and pro genes was shown to be involved in the ribosomal frameshifting event for the synthesis of protease. To mimic the formation of the 76-kilodalton gag-pro precursor polyprotein formed by ribosomal slipping, the coding frames of the gag and pro gene were adjusted. The processing of the gag-pro precursor polyprotein depended on an intact protease gene, implying that a cis-acting function of human T-cell leukemia virus type I protease may be necessary to trigger the initial cleavage event that leads to the release of protease from the precursor protein.
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PMID:Processing of gag precursor polyprotein of human T-cell leukemia virus type I by virus-encoded protease. 284 70

The plasma membrane of murine erythro-leukemia (MEL) cells contains a 140-kD protein that binds specifically to fibronectin. A 125I-labeled 140-kD protein from surface-labeled uninduced MEL cells was specifically bound by an affinity matrix that contained the 115-kD cell binding fragment of fibronectin, and specifically eluted by a synthetic peptide that has cell attachment-promoting activity. The loss of this protein during erythroid differentiation was correlated with loss of cellular adhesion to fibronectin. Both MEL cells and reticulocytes attached to the same site on fibronectin as do fibroblasts since adhesion of erythroid cells to fibronectin was specifically blocked by a monoclonal antibody directed against the cell-binding fragment of fibronectin and by a synthetic peptide containing the Arg-Gly-Asp-Ser sequence found in the cell-binding fragment of fibronectin. Erythroid cells attached specifically to surfaces coated either with the 115-kD cell-binding fragment of fibronectin or with the synthetic peptide-albumin complex. Thus, the erythroid 140-kD protein exhibits several properties in common with those described for the fibronectin receptor of fibroblasts. We propose that loss or modification of this protein at the cell surface is responsible for the loss of cellular adhesion to fibronectin during erythroid differentiation.
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PMID:The fibronectin receptor on mammalian erythroid precursor cells: characterization and developmental regulation. 293 41

Rat mast cells and a neoplastic analogue such as rat basophilic leukemia (RBL) cells have receptors that have exceptionally high affinity for immunoglobulin E (IgE). When aggregated, these receptors induce cellular degranulation. The alpha chain of the receptor contains the binding site for IgE; the function(s) of the noncovalently associated beta and gamma chains is (are) still undefined. Using a cDNA library constructed from the mRNA of RBL cells, we have isolated a cDNA clone whose sequence predicts a putative 23-residue signal peptide, followed by a sequence that accurately predicts the amino acid composition, the peptide molecular weight, and six peptide sequences (encompassing 59 residues or 26% of the total number) determined for the alpha chain by direct analysis. These findings provide strong evidence that the cDNA codes for the alpha chain, even though expression has not been unambiguously achieved. The sequence suggests that the alpha chain contains a 180-residue extracellular portion with two homologous domains of approximately 35 residues, a 20-residue transmembrane segment containing an aspartic acid, and a 27-residue cytoplasmic portion containing 9 basic amino acids. The sequence shows no homology with the low-affinity receptor for IgE from lymphocytes but over 30% homology with an Fc gamma receptor.
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PMID:A cDNA presumptively coding for the alpha subunit of the receptor with high affinity for immunoglobulin E. 295 18

Sequence analysis of the mutant Dbm13, Dbm14, and Dbm24 genes indicate that they differ from the parental Db gene by 4, 1, and 8 nucleotides, respectively. The mutant sequences substituted into Dbm13 and Dbm24 are identical to those found in the Kb gene, at the homologous positions. Thus, similar to the Kb gene, the Db gene is able to undergo micro-recombination (gene conversion) events with other class I genes. Such data suggest that micro-recombination events could be an important mechanism for the diversification of all H-2 genes. The Db mutant products share a common theme: the alterations in all occur at amino acid residues whose side chains in the homologous class I HLA-A2 molecule project into the postulated peptide antigen-binding cleft, and hence, would be expected to alter the binding of foreign or self peptides. Due to such changes, the bm14 mouse has become a nonresponder in the CTL response to Moloney murine leukemia virus (M-MuLV), as the alteration of one amino acid residue at position 70 (a Gln to His) is sufficient to entirely abrogate the cell-mediated response to the virus. On the other hand, the bm13 mouse has shifted the major part of its M-MuLV restriction to Kb, a profound alteration in CTL responsiveness due to the alteration of three amino acids (Leu to Gln at 114, Phe to Tyr at 116, and Glu to Asp at 119) in a peptide stretch of beta-pleated sheet structure lining the bottom of the antigen-binding cleft. Thus, study of these mutants reveals that, in one step, micro-recombination at the genetic level has resulted at the protein level in profound changes in the immune response to viral infection. Such a mechanism operating at the population level can be a driving force during evolution for modulating the character of CTL immunity.
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PMID:Three spontaneous H-2Db mutants are generated by genetic micro-recombination (gene conversion) events. Impact on the H-2-restricted immune responsiveness. 319 70

Activation of the cellular oncogene c-N-ras has been frequently observed in DNA from leukemic cells in acute myeloid leukemia (AML). Ras gene activation sufficient to mediate in vitro transformation and rodent tumorigenesis usually results from point mutations and amino acid substitutions in the 12th or 61st codons. In AML and the related myelodysplastic syndromes, amino acid substitution at the 13th codon has been observed. An activated c-N-ras gene from a 45-year-old patient with AML was isolated by transfection analysis and subjected to molecular cloning and sequence analysis. A point mutation of the 12th codon (GGT to GAT) resulting in aspartic acid substitution for glycine was observed. In other neoplasms such as colon cancer, specific ras mutations occur predominantly (e.g., K-ras, codon 12). This predominance has been of demonstrable value in analyzing large cohorts for ras activation with techniques that are rapid and economical, such as oligonucleotide hybridization. It had previously been thought that such a predominance for activation of c-N-ras at codon 13 existed in AML; however, this study in concert with others underscores the importance of 12th codon c-N-ras mutations, along with 13th and 61st codon mutations in the molecular pathogenesis of AML. Guanylate to adenylate transition mutations are commonly observed in AML and may provide insight into potential environmental leukemogens. Addressing all commonly prevalent ras activating mutations bears impact in the future design of molecular surveys of the role of ras activation in leukemogenesis.
Leukemia 1988 Feb
PMID:12th codon mutation resulting in c-N-ras activation in acute myelogenous leukemia. 327 72

It has been found that leukemia cells can be induced by various agents [e.g., by retinoic acid (RA)] to mature to a nonproliferative end stage. It has also been found that normal mature granulocytes produce a chalone-like "hemoregulatory peptide (HP)" which seems to be involved in the inhibitory proliferation control of myelopoietic cells. In view of the intended use of maturation induction treatment as an alternative to current antileukemic therapy it appeared to be of interest to know if granulocytes, obtained by RA treatment of the promyelocytic leukemia cell line HL-60, would produce normal HP or if their transformed phenotype would cause production of deviant regulatory peptide(s). It was found that conditioned media from RA-treated HL-60 cells inhibited myeloid proliferation but strongly stimulated the growth of erythroid and lymphoid cells. A low molecular weight thiol-containing peptide was isolated which inhibited colony formation by normal granulocyte-macrophage committed stem cells but unlike HP had no effect on (untreated) HL-60 cells themselves. It was also shown that the HL-60 RA peptide is chemically different from HP in terms of molecular size, electrophoretic mobility, composition, and NH2-terminal sequence, which was determined as glutamine-aspartic acid-proline. It is concluded that differentiated HL-60 cells produce hemoregulatory factor(s) with properties different from those of normal HP. The implication of a possible abnormal regulatory behavior of induced leukemic populations is discussed with respect to leukemia therapy by differentiation induction.
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PMID:Identification of a regulatory peptide distinct from normal granulocyte-derived hemoregulatory peptide produced by human promyelocytic HL-60 leukemia cells after differentiation induction with retinoic acid. 346 Jun 96

The synthetic pentapeptide pGlu-Glu-Asp-Cys-Lys has recently been proposed as the active component of a granulocyte-derived inhibitor of normal haematopoiesis. We investigated its biological activity on leukaemic myelopoiesis both in vitro and in vivo in rats. Three different human permanent myeloid leukaemic cell lines (HL60, KG1, ML3) and a rat transplantable acute myeloid leukaemia (Shay leukaemia) were studied. Neither HL60 nor KG1 were sensitive to the peptide whereas a consistently reproducible inhibition of 3H-TdR uptake was observed in ML3 cells. This effect was not due to a unspecific toxic action on target cells and was spontaneously reversible. When injected i.p. twice daily at an appropriate concentration in rats bearing Shay leukaemia, the peptide caused a significant increase in survival. Our results therefore indicate that the synthetic pentapeptide studied inhibits not only normal but also leukaemic myelopoiesis.
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PMID:Inhibitory activity of a synthetic pentapeptide on leukaemic myelopoiesis both in vitro and in vivo in rats. 348 Feb 37


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