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 stem cell leukaemia (SCL) gene is a member of the basic helix-loop-helix family of transcription factors and is essential for the development of all haematopoietic lineages. SCL is expressed in pluripotent haematopoietic stem cells and also following commitment to the erythroid, mast and megakaryocytic lineages. The mechanisms responsible for this pattern of expression are poorly understood, but are likely to illuminate the molecular basis for stem cell development and lineage commitment. Here we present the first description of the regulation of the SCL gene in mast cells. In this study we systematically analysed the chromatin structure of a 45 kb region of the murine SCL locus in mast cells. The pattern of DNase 1 and restriction endonuclease hypersensitive sites in mast cells was distinct from, but overlapped with, the pattern previously described in erythroid and primitive myeloid cells. Each potential regulatory element was tested using transient reporter assays to assess their functional significance in mast cells. These studies identified two potent enhancers, one of which was downstream of the SCL gene. Further characterisation of this 3' enhancer demonstrated that it required the presence of two distinct DNase 1 hypersensitive sites for full activity, and that it was capable of stimulating transcription from both promoter 1a and 1b. Since the 3' enhancer is active in both erythroid and mast cells, it will now be important to see whether it is independently activated in these lineages, or whether it is also active in haematopoietic stem cells.
Leukemia 1999 May
PMID:Chromatin structure and transcriptional regulation of the stem cell leukaemia (SCL) gene in mast cells. 1037 80

Hydroxymethylacylfulvene (HMAF, MGI 114) is a novel antitumor drug and a potent pro-apoptotic agent that has the potential to alkylate cellular nucleophiles. The objective of these studies was to characterize drug uptake and cellular targets for drug binding in human leukemia CEM cells. The uptake of [14C]HMAF had two components: a rapid phase (0-10 min) and a slow phase. At 10 microM drug (37 degrees), the rapid and slower phase amounted to 0.86 and 0.13 pmol/min/10(6)cells, respectively. HMAF uptake was inhibited 82% by low temperature (4 degrees) at 4 hr. Cell-associated HMAF localized to nuclear (50%), cytoplasmic (37%), and membrane fractions (10%). Continued drug uptake appeared to be driven by covalent binding to cellular macromolecules. Approximately 1/4 and 2/3 of cell-associated HMAF formed covalent adducts after 10 min and 4 hr, respectively, as found by perchloric acid precipitation. Drug adducts were not readily reversible; 77% of the covalently bound radiolabel was retained by the cells 20 hr after drug treatment. Combinations of DNase, RNase, and proteinase K with perchloric acid precipitation showed that approximately 60, 30, and 10% of the covalently bound drug was associated with the protein, DNA, and RNA fractions, respectively. Incubation of 100 microM [14C]HMAF (24 hr) with purified DNA, serum albumin, thioredoxin, and thioredoxin reductase resulted in 6, 22, 14, and 11 pmol [14C]HMAF/microg DNA or protein, respectively. Results indicate that multiple targets for HMAF binding may contribute to the pro-apoptotic and antiproliferative action of the drug.
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PMID:Drug uptake and cellular targets of hydroxymethylacylfulvene (HMAF). 1042 61

: From the coral Galaxea fascicularis, a crude mucus-like extract (MS) and subsequently its purified component (P6) appear to contain a DNase-like activity that indiscriminately digested lambdaDNA, as well as naked genomic DNAs isolated from a multiple-drug-resistant murine leukemia cell line, P388/VCR, and a nontransformed liver cell line, BL8L. However, MS and P6 specifically induced in situ DNA digestion in cultured P388/VCR cells from 30 minutes onward. After 3 days of incubation with MS or P6, DNA degradation coincided with complete killing of P388/VCR. In situ fluorescent labeling of fragmented DNA revealed that P6 induced apoptosis of P388/VCR cells, occurring as early at 1.5 hours. By day 3, all the P6-treated leukemia cells were apoptotic. In contrast, P6 caused neither in situ DNA digestion, nor apoptosis in the untransformed BL8L cells. Whether the DNase-like action of P6 is independent of or responsible for triggering the intrinsic endonuclease activity in the leukemia cell, thus leading to apoptosis, remains an object for further research. Nevertheless, the specificity of the apoptotic action of P6 on P388/VCR cells indicates its potential role in the development of an anticancer agent.
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PMID:Novel Bioactivities from a Coral, Galaxea fascicularis: DNase-like Activity and Apoptotic Activity Against a Multiple-Drug-Resistant Leukemia Cell Line. 1048 7

The human AF9 gene at 9p22 is one of the most common fusion partner genes with the MLL gene at 11q23, resulting in the t(9;11)(p22;q23). The MLL-AF9 fusion gene is associated with de novo acute myelo-genous leukemia (AML), rarely with acute lymphocytic leukemia (ALL) and with therapy related leukemia (t-AML). The AF9 gene is >100 kb and two patient breakpoint cluster regions (BCRs) have been identified; BCR1 is within intron 4, previously called site A, whereas BCR2 or site B spans introns 7 and 8. Patient breakpoint locations were determined previously by RT-PCR and by genomic DNA cloning. In this study, we defined the exon-intron boundaries and identified several different structural elements in AF9 including a co-localizing in vivo DNA topo II cleavage site and an in vitro DNase I hypersensitive (DNase 1 HS) site in intron 7 in BCR2. Reversibility experiments demonstrated a religation of the topo II cleavage sites. The location of the in vivo topo II cleavage site was confirmed in vitro using a topo II cleavage assay. In addition, two scaffold associated regions (SARs) are located centromeric to the topo II and DNase I HS cleavage sites and border both patient breakpoint regions: SAR1 is located in intron 4, whereas SAR2 encompasses parts of exons 5-7. This study demonstrates that the patient breakpoint regions of AF9 share the same structural elements as the MLL BCR. We describe a DNA breakage and repair model for non-homologous recombination between MLL and its partner genes, particularly AF9.
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PMID:DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis. 1086 Dec 94

Conjugate DNAzymes were synthesized by solid phase fragment condensation and their biological properties were characterized. They have increased affinity to target RNA, enhanced stability against DNase 1 digestion and comparable or higher RNA cleaving activity compared with native and also phosphorothioate DNA zymes. It was also demonstrated that conjugate DNAzymes could inhibit BCR-ABL tyrosine kinase in cellular lysis of human leukemia cell line. Consequently DNAzymes can be expected to act effectively in cellular system and also in vivo system.
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PMID:Conjugate DNAzymes. 1451 Apr 38

We showed that a U5-U3 junction was reproducibly detected by a PCR assay as early as 1 to 2 h postinfection with a DNase-treated murine leukemia virus (MLV)-containing supernatant in aphidicolin-arrested NIH 3T3 cells, as well as in nonarrested cells. Such detection is azidothymidine sensitive and corresponded to neosynthesized products of the reverse transcriptase. This observation was confirmed in two additional human cell lines, TE671 and ARPE-19. Using cell fractionation combined with careful controls, we found that a two-long-terminal-repeat (two-LTR) junction molecule was detectable in the cytoplasm as early as 2 h post virus entry. Altogether, our data indicated that the neosynthesized retroviral DNA led to the early formation of structures including true two-LTR junctions in the cytoplasm of MLV-infected cells. Thus, the classical assumption that two-LTR circles are a mitosis-dependent dead-end product accumulating in the nucleus must be reconsidered. MLV-derived products containing a two-LTR junction can no longer be used as an exclusive surrogate for the preintegration complex nuclear translocation event.
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PMID:Early detection of a two-long-terminal-repeat junction molecule in the cytoplasm of recombinant murine leukemia virus-infected cells. 1516 12

Xenotropic murine leukemia virus-related virus (XMRV) is a new human gammaretrovirus identified in prostate cancer tissue from patients homozygous for a reduced-activity variant of the antiviral enzyme RNase L. Neither a casual relationship between XMRV infection and prostate cancer nor a mechanism of tumorigenesis has been established. To determine the integration site preferences of XMRV and the potential risk of proviral insertional mutagenesis, we carried out a genome-wide analysis of viral integration sites in the prostate cell line DU145 after an acute XMRV infection and compared the integration site pattern of XMRV with those found for murine leukemia virus and two human retroviruses, human immunodeficiency virus type 1 and human T-cell leukemia virus type 1. Among all retroviruses analyzed, XMRV has the strongest preference for transcription start sites, CpG islands, DNase-hypersensitive sites, and gene-dense regions; all are features frequently associated with structurally open transcription regulatory regions of a chromosome. Analyses of XMRV integration sites in tissues from prostate cancer patients found a similar preference for the aforementioned chromosomal features. Additionally, XMRV integration sites in cancer tissues were associated with cancer breakpoints, common fragile sites, microRNA, and cancer-related genes, suggesting a selection process that favors certain chromosomal integration sites. In both acutely infected cells and cancer tissues, no common integration site was detected within or near proto-oncogenes or tumor suppressor genes. These results are consistent with a model in which XMRV may contribute to tumorigenicity via a paracrine mechanism.
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PMID:Integration site preference of xenotropic murine leukemia virus-related virus, a new human retrovirus associated with prostate cancer. 1868 13

Tumor necrosis factor alpha (TNF-alpha) and lymphotoxin alpha (LT-alpha) have been shown to play an important role in the pathogenesis of limphoproliferative disease. Both cytokines regulate cell-survival and cell-death in leukemic cells. TNF-alpha and LT-alpha are highly produced in chronic lymphotic leukemia (CLL) and non-Hodgkin lymphoma (NHL) patients. Genetic polymorphism within regulatory regions of these cytokine genes can alter their expression levels. This study investigates an influence of TNF-alpha - 308 and LT-alpha + 250 polymorphisms on the activity of alkaline DNase in mononuclear cells of both patient groups as a potent biochemical marker of DNA fragmentation in the terminal phase of apoptosis. Study was performed on mononuclear cells of CLL and NHL patients. SNP were obtained by PCR-RFLP method. The activity of alkaline DNase was measured by spectrophotometric method. The study provided evidence of the influence of TNFG/A genotype and A alleles in the susceptibility to NHL, since the association of LT-alphaG/G genotype with CLL was observed. High-producing TNF-alpha - 308/LT-alpha + 250 heterozygous haplotype is associated with high NHL incidence. The investigated SNP influence the activity of alkaline DNase in CLL and NHL patients. The observed polymorphisms may modulate susceptibility of leukemic cells to apoptosis by way of DNase activity.
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PMID:Polymorphisms of tumor-necrosis factor-alpha - 308 and lymphotoxin-alpha + 250: possible modulation of susceptibility to apoptosis in chronic lymphocytic leukemia and non-Hodgkin lymphoma mononuclear cells. 1902 Oct 60

Methadone (d,l-methadone hydrochloride) is a full-opioid agonist, originally developed as a substitution for heroin or other opiates abusers. Nowadays methadone is also being applied as long-lasting analgesics in cancer, and it is proposed as a promising agent for leukemia therapy. Previously, we have demonstrated that high concentrations of methadone (0.5mM) induced necrotic-like cell death in SH-SY5Y cells. The pathway involved is caspase-independent but involves impairment of mitochondrial ATP synthesis and mitochondrial cytochrome c release. However, the downstream mitochondrial pathways remained unclear. Here, we studied the participation of apoptosis inducing factor (AIF) in methadone-induced cell death. Methadone resulted in a translocation of AIF from mitochondria to the nucleus. Translocation was inhibited by cyclosporine A, but not by lack of Bax protein. Therefore the effect seems mediated by the formation of the mitochondrial transition pore, but is apparently independent of Bax. Furthermore, methadone-treated SH-SY5Y nuclei show characteristics that are typical for stage I nuclear condensation. Methadone did not induce degradation of DNA into oligonucleosomal fragments or into high molecular weight DNA fragments. Absence of DNA fragmentation coincided with a considerable decrease in the levels of the caspase-actived endonuclase DNase and its chaperone-inhibitor ICAD. In conclusion, our results provide mechanistic insights into the molecular mechanisms that underlie methadone-induced cell death. This knowledge may prove useful to develop novel strategies to prevent toxic side-effects of methadone thereby sustaining its use as therapeutical agent against tumors.
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PMID:Methadone induces CAD degradation and AIF-mediated necrotic-like cell death in neuroblastoma cells. 2114 98

The analysis of genomic distribution of retroviral vectors is a powerful tool to monitor 'vector-on-host' effects in gene therapy (GT) trials but also provides crucial information about 'host-on-vector' influences based on the target cell genetic and epigenetic state. We had the unique occasion to compare the insertional profile of the same therapeutic moloney murine leukemia virus (MLV) vector in the context of the adenosine deaminase-severe combined immunodeficiency (ADA-SCID) genetic background in two GT trials based on infusions of transduced mature lymphocytes (peripheral blood lymphocytes, PBL) or a single infusion of haematopoietic stem/progenitor cells (HSC). We found that vector insertions are cell-specific according to the differential expression profile of target cells, favouring, in PBL-GT, genes involved in immune system and T-cell functions/pathways as well as T-cell DNase hypersensitive sites, differently from HSC-GT. Chromatin conformations and histone modifications influenced integration preferences but we discovered that only H3K27me3 was cell-specifically disfavoured, thus representing a key epigenetic determinant of cell-type dependent insertion distribution. Our study shows that MLV vector insertional profile is cell-specific according to the genetic/chromatin state of the target cell both in vitro and in vivo in patients several years after GT.
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PMID:Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell. 2124 17


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