Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While many advances have been made in the treatment of patients with cancer, significant challenges that remain include tumor cell resistance and the toxicity associated with currently used intensive chemotherapeutic regimens. This is particularly true for patients with acute myelogenous leukemia (AML). Most patients with AML usually are able to achieve complete remission, but only a minority obtain long-term survival. In addition, much of the success achieved has been due to escalation of chemotherapeutic dosing and hematopoietic stem cell transplantation. There is thus a great need for improved therapies which would ideally be able to circumvent drug resistance and more specifically target leukemic cells. Advances in immunobiology over the past century have led to new hope for the development of immune-mediated vaccine therapies for patients with cancer. This review focuses on the development of vaccine approaches for treatment of AML and some of the potential advantages and problems.
J Mol Med (Berl) 1998 Feb
PMID:The potential for antitumor vaccination in acute myelogenous leukemia. 950 Jun 73

Association of transcription factors with the nuclear matrix represents a mechanism by which nuclear architecture may influence transcriptional control of gene expression. This investigation examines nuclear matrix associated proteins (NMP's) isolated from ocular lens epithelial cells by monitoring DNA binding activities using consensus oligonucleotides recognized by the transcription factors YY1, AML-1, AP-1, SP-1 and ATF. The nuclear matrix fractions tested included an immortilized human lens epithelial cell line containing the SV40 large T-antigen, and two mouse lens epithelial cell lines derived from either a normal mouse or a cataract mouse. A rabbit epidermal epithelial cell line and HeLa cells were also included in this study for comparison. The data from these experiments reveal that ubiquitously represented and tissue restricted regulatory proteins are associated with nuclear matrix of lens epithelial cells. The functional significance of the nuclear matrix association of these transcription factors remains to be determined. However, our findings raise the possibility that the transcription factors associated with the nuclear matrix could have specific roles in gene regulation and eye tissue development.
Mol Biol Rep 1998 Jan
PMID:Nuclear matrix associated DNA-binding proteins of ocular lens epithelial cells. 954 63

Acute myeloid leukaemia (AML) may not only occur as a de novo disease but may evolve from a preceding myelodysplastic syndrome (MDS) or may result from therapy for a previous malignancy. These secondary acute myeloid leukaemias (sAML) possess some common biological and clinical features of the corresponding de novo disorders. The cytokine interleukin-1 (IL-1) is known to have a role in haematopoiesis, and modulation of its action might contribute to the deregulation of proliferation seen in leukaemia. It has recently been reported that a variable number tandem repeat (VNTR) polymorphism in the IL-1 receptor antagonist (IL-1ra) gene is closely associated with the severity of many inflammatory and autoimmune diseases, and may also play a role in the pathogenesis of sAML. We sought to confirm this finding in a large group of patients classified as having sAML. We found no differences in either the genotypic or allele frequencies of the polymorphism studied when compared with those of normal controls or other haematological disorders. No differences were observed in allele frequencies between younger and older patients, or between those patients who had an antecedent myelodysplasia and those who had received prior chemotherapy or radiotherapy. We conclude that the described polymorphism in the IL-1ra gene is not associated with the development of sAML.
Cytokines Cell Mol Ther 1998 Mar
PMID:IL-1 receptor antagonist gene polymorphism in patients with secondary acute myeloid leukaemia. 955 11

Chromosomal translocations in acute leukemia that affect the AML-1/CBFbeta transcription factor complex create dominant inhibitory proteins. However, the mechanisms by which these proteins act remain obscure. Here we demonstrate that the multidrug resistance 1 (MDR-1) promoter is a target for AML/ETO transcriptional repression. This repression is of basal, not activated, expression from the MDR-1 promoter and thus represents a new mechanism for AML/ETO function. We have defined two domains in AML/ETO that are required for repression of basal transcription from the MDR-1 promoter: a hydrophobic heptad repeat (HHR) motif and a conserved zinc finger (ZnF) domain termed the MYND domain. The HHR mediates formation of AML/ETO homodimers and AML/ETO-ETO heterodimers. Single serine substitutions at conserved cysteine residues within the predicted ZnFs also abrogate transcriptional repression. Finally, we observe that AML/ETO can also inhibit Ets-1 activation of the MDR-1 promoter, indicating that AML/ETO can disrupt both basal and Ets-1-dependent transcription. The fortuitous inhibition of MDR-1 expression in t(8;21)-containing leukemias may contribute to the favorable response of these patients to chemotherapeutic drugs.
Mol Cell Biol 1998 Jun
PMID:The MYND motif is required for repression of basal transcription from the multidrug resistance 1 promoter by the t(8;21) fusion protein. 958 1

The polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor (CBF) is a transcription factor composed of two subunits, alpha and beta. The gene encoding the beta subunit is disrupted by inv(16), resulting in the formation of a chimeric protein, beta-SMMHC, which is associated with acute myelogenous leukemia. To understand the effect of beta-SMMHC on PEBP2-mediated transactivation, we used a luciferase assay system in which contribution of both the alpha and beta subunits was absolutely required to activate transcription. Using this system, we found that the minimal region of the beta subunit required for transactivation resides between amino acid 1 and 135, which is known to dimerize with the alpha subunit. In contrast, beta-SMMHC, despite having this minimal region for dimerization and transactivation, failed to support transcription with the alpha subunit. Furthermore beta-SMMHC blocked the synergistic transcription achieved by PEBP2 and CCAAT/enhancer binding protein alpha. By using a construct in which the PEBP2 alpha subunit was fused to the glucocorticoid receptor ligand binding domain, we demonstrated that coexpressed beta-SMMHC tightly sequestered the alpha subunit in the cytoplasm and blocked dexamethasone-dependent nuclear translocation of the alpha subunit. Thus, the result suggess that beta-SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the alpha subunit. Lastly proliferation of ME-1 cells that harbor inv(16) was blocked by an antisense oligonucleotide complementary to the junction of the chimeric mRNA, suggesting that beta-SMMHC contributes to leukemogenesis by blocking the differentiation of myeloid cells.
Mol Cell Biol 1998 Jul
PMID:Cytoplasmic sequestration of the polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor alpha (CBFalpha) subunit by the leukemia-related PEBP2/CBFbeta-SMMHC fusion protein inhibits PEBP2/CBF-mediated transactivation. 963 9

The effect of cytokine transduction on the tumorigenicity and immunogenicity of murine non-immunogeneic mammary carcinoma (4T1), acute myeloid leukemia (mAML) and partially immunogenic B-cell leukemia (BCL1) has been evaluated in syngeneic strains of mice. Transduction by retroviral vectors containing the genes for GM-CSF, IL-2 or IFN-gamma did not lead to a marked antitumor effect in 4T1 mammary tumor or BCL1. A reduced local tumor size was observed in mice inoculated with 4T1 cells transduced with both GM-CSF and IL-2 genes followed by an in vitro exposure to recombinant IFN-gamma, but survival was not prolonged. Tumorigenicity of mAML cells transduced with the gene coding for IFN-gamma was significantly reduced as manifested by prolonged survival of mice in comparison with animals inoculated with non-transduced mAML cells. Transduction by each of the aforementioned cytokines did not affect the immunogenicity of these tumor model cells. The results suggest that genetic modification of spontaneous and non-immunogenic experimental tumor models does not necessarily support direct utilization of cytokine gene therapy for clinical application. More effective methods have yet to be established in order to achieve an antitumor effect in spontaneous non-immunogenic malignancies.
Cytokines Cell Mol Ther 1998 Jun
PMID:Cytokine gene transduction into non-immunogeneic murine tumor cells. 968 Dec 47

The primary role of protooncogene c-kit in mast cell differentiation is supported by the development of mast cells from CD34+/CD117+(c-kit) myeloid precursors. Growth factor independence, neoplastic transformation and differentiation of mast cells were found in association with c-kit activating mutations in both murine and human mastocytoma and mast cell diseases. We have identified a novel c-kit mutation (D816Y) in peripheral blood mononuclear cells from a patient with AML (M2), massive presence of mast cells in bone marrow and rapid progression of the disease. The mutation, a G-->T transversion at nt 2467 of the c-kit gene resulting in Asp816-->Tyr substitution, corresponds to the D814Y and D817Y mutations identified and characterized in the murine P815 mastocytoma and the rat RBL-2H3 mast cell leukemia cell lines. The absence of SCF transcripts that we found by RTPCR in the patient's blasts indicates that, also in humans, this activating mutation leads to SCF independent growth. The expression of the mutant allele on Kit signaling may be further enhanced by trisomy of chromosome 4 (carrying the c-kit gene) in the patient's blasts. From these findings it is concluded that mast cells could be generated from a leukemic CD34/CD117-positive clone, that combines the antigenic expression of mast cell precursor to the growth and differentiation factor-independence which was derived by the c-kit D816Y mutation.
Blood Cells Mol Dis 1998 Jun
PMID:In vivo differentiation of mast cells from acute myeloid leukemia blasts carrying a novel activating ligand-independent C-kit mutation. 971 3

Myeloperoxidase (MPO), an iron-containing heme protein localized in the azurophilic granules of neutrophil granulocytes and in the lysosomes of monocytes, is involved in the killing of several micro-organisms and foreign cells, including bacteria, fungi, viruses, red cells, and malignant and nonmalignant nucleated cells. Despite the primary role of the oxygen-dependent MPO system in the destruction of certain phagocytosed microbes, subjects with total or partial MPO deficiency generally do not have an increased frequency of infections, probably because other MPO-independent mechanism(s) for microbicidal activity compensate for the lack of MPO. Infectious diseases, especially with species of Candida, have been observed predominantly in MPO-deficient patients who also have diabetes mellitus, but the frequency of such cases is very low, less than 5% of reported MPO-deficient subjects. Evidence from a number of investigators indicates that individuals with total MPO deficiency show a high incidence of malignant tumors. Since MPO-deficient PMNs exhibit in vitro a depressed lytic action against malignant human cells, it can be speculated that the neutrophil MPO system plays a central role in the tumor surveillance of the host. However, any definitive conclusion on the association between MPO deficiency and the occurrence of cancers needs to be confirmed in further clinical studies. Clinical manifestations of this disorder depend on the nature of the defect; an acquired abnormality associated with other hematological or nonhematological diseases has been occasionally described, but the primary deficiency is the form more commonly reported. Another area of interest pertinent to MPO expression is related to the use of anti-MPO monoclonal antibodies for the lineage assignment of acute leukemic cells, the definition of FAB MO acute myeloid leukemia, the identification of biphenotypic acute leukemias, and their distinction from acute leukemia with minimal phenotypic deviation. The advantage of MPO monoclonal antibodies over the MPO cytochemical assay relies in the ability of the former method to recognize the enzymatically inactive precursor forms of MPO.
J Mol Med (Berl) 1998 Sep
PMID:Clinical manifestation of myeloperoxidase deficiency. 976 45

t(8;21) is one of the most frequent translocations associated with acute myeloid leukemia. It produces a chimeric protein, acute myeloid leukemia-1 (AML-1)-eight-twenty-one (ETO), that contains the amino-terminal DNA binding domain of the AML-1 transcriptional regulator fused to nearly all of ETO. Here we demonstrate that ETO interacts with the nuclear receptor corepressor N-CoR, the mSin3 corepressors, and histone deacetylases. Endogenous ETO also cosediments on sucrose gradients with mSin3A, N-CoR, and histone deacetylases, suggesting that it is a component of one or more corepressor complexes. Deletion mutagenesis indicates that ETO interacts with mSin3A independently of its association with N-CoR. Single amino acid mutations that impair the ability of ETO to interact with the central portion of N-CoR affect the ability of the t(8;21) fusion protein to repress transcription. Finally, AML-1/ETO associates with histone deacetylase activity and a histone deacetylase inhibitor impairs the ability of the fusion protein to repress transcription. Thus, t(8;21) fuses a component of a corepressor complex to AML-1 to repress transcription.
Mol Cell Biol 1998 Dec
PMID:ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. 981 4

Nuclear receptor corepressor (CoR)-histone deacetylase (HDAC) complex recruitment is indispensable for the biological activities of the retinoic acid receptor fusion proteins of acute promyelocytic leukemias. We report here that ETO (eight-twenty-one or MTG8), which is fused to the acute myelogenous leukemia 1 (AML1) transcription factor in t(8;21) AML, interacts via its zinc finger region with a conserved domain of the corepressors N-CoR and SMRT and recruits HDAC in vivo. The fusion protein AML1-ETO retains the ability of ETO to form stable complexes with N-CoR/SMRT and HDAC. Deletion of the ETO C terminus abolishes CoR binding and HDAC recruitment and severely impairs the ability of AML1-ETO to inhibit differentiation of hematopoietic precursors. These data indicate that formation of a stable complex with CoR-HDAC is crucial to the activation of the leukemogenic potential of AML1 by ETO and suggest that aberrant recruitment of corepressor complexes is a general mechanism of leukemogenesis.
Mol Cell Biol 1998 Dec
PMID:Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. 981 5


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