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)

Acute leukemias arise secondary to chromosomal aberrations that cause dysfunctions in gene regulation and regulatory factors. Significant differences in morphology between acute leukemic and nonleukemic hematopoietic cells are readily observed. How morphologic changes of the nuclei of acute leukemic cells relate to the underlying functional alterations of gene expression is minimally understood. Spatial modifications in the representation and/or organization of regulatory factors may be functionally linked to perturbations of gene expression in acute leukemic cells. Using in situ immunofluorescence microscopy, we addressed the interrelationships of modifications in nuclear morphology with the intranuclear distribution of leukemia-related regulatory factors (including ALL-1, PML, and AF-9) in cells from patients with acute leukemia. We compared the localization of leukemia-associated proteins with various factors involved in gene transcription and RNA processing (e.g., RNA polymerase II and SC-35). Our findings suggest that there are leukemia-associated aberrations in mechanisms that direct regulatory factors to sites within the nucleus. This misplacement of key cognate factors may contribute to perturbations in gene expression characteristic of leukemias.
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PMID:Modified intranuclear organization of regulatory factors in human acute leukemias: reversal after treatment. 1067 14

Gene CBP codes for a transcriptional coactivator, which can interact with many transcriptional factors. It modifies the process of transcription stimulated by these factors by specific binding to RNA polymerase II holoenzyme or by histone acetylation. CBP gene mutation is the molecular cause of autosomal dominant genetic disease called Rubinstein-Taybi syndrome that is manifested by mental and growth retardations, by typical face malformations and broad thumbs and broad big toes. The CBP gene can be affected by the t(8;16)(p11;p13.3) translocation resulting in production of the MOZ/CBP chimeric protein and in induction of acute myeloblastic leukaemia. Therapy using topoisomerase II inhibitors can induce the t(11;16)(q23;13.3) translocation causing acute myeloid or lymphoid leukaemia or myelodysplasia through production of the MLL/CBP protein chimera.
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PMID:[Clinical sequelae of mutation of the CBP gene]. 1074 38

The translocation liposarcoma (TLS) gene is fused to the ETS-related gene (ERG) in human myeloid leukemia, resulting in the generation of a TLS-ERG protein. We demonstrate that both TLS and the TLS-ERG leukemia fusion protein bind to RNA polymerase II through the TLS N-terminal domain, which is retained in the fusion protein; however, TLS recruits members of the serine-arginine (SR) family of splicing factors through its C-terminal domain, whereas the TLS-ERG fusion protein lacks the ability to recruit SR proteins due to replacement of the C-terminal domain by the fusion partner ERG. In transient-transfection assays, the TLS-ERG fusion protein inhibits E1A pre-mRNA splicing mediated by these TLS-associated SR proteins (TASR), and stable expression of the TLS-ERG fusion protein in K562 cells alters the splicing profile of CD44 mRNA. These results suggest that TLS fusion proteins may lead to cellular abnormalities by interfering with the splicing of important cellular regulators.
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PMID:TLS-ERG leukemia fusion protein inhibits RNA splicing mediated by serine-arginine proteins. 1077 24

Eukaryotic mRNA synthesis is catalyzed by multisubunit RNA polymerase II and proceeds through multiple stages referred to as preinitiation, initiation, elongation, and termination. Over the past 20 years, biochemical studies of eukaryotic mRNA synthesis have largely focused on the preinitiation and initiation stages of transcription. These studies led to the discovery of the class of general initiation factors (TFIIB, TFIID, TFIIE, TFIIF, and TFIIH), which function in intimate association with RNA polymerase II and are required for selective binding of polymerase to its promoters, formation of the open complex, and synthesis of the first few phosphodiester bonds of nascent transcripts. Recently, biochemical studies of the elongation stage of eukaryotic mRNA synthesis have led to the discovery of several cellular proteins that have properties expected of general elongation factors and that have been found to play unanticipated roles in human disease. Among these candidate general elongation factors are the positive transcription elongation factor b (P-TEFb), eleven-nineteen lysine-rich in leukemia (ELL), Cockayne syndrome complementation group B (CSB), and elongin proteins, which all function in vitro to expedite elongation by RNA polymerase II by suppressing transient pausing or premature arrest by polymerase through direct interactions with the elongation complex. Despite their similar activities in elongation, the P-TEFb, ELL, CSB, and elongin proteins appear to play roles in a diverse collection of human diseases, including human immunodeficiency virus-1 infection, acute myeloid leukemia, Cockayne syndrome, and the familial cancer predisposition syndrome von Hippel-Lindau disease. here we review our current understanding of the P-TEFb, ELL, CSB, and elongin proteins, their mechanisms of action, and their roles in human disease.
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PMID:Transcription elongation and human disease. 1087 52

Retroviruses use RNA as their genetic material within viral particles and DNA (provirus) as their genetic material within cells. The rate of recombination during reverse transcription between two identical sequences within the same RNA molecule is very high. In this study, we have developed a sensitive system to study recombination occurring within the proviral sequence. This system includes a murine Moloney leukemia virus vector which contains a neomycin resistance gene (neo) and two mutated green fluorescent protein genes (gfp) in tandem positions. The 3' end of the first gfp and the 5' end of the second gfp gene are both mutated, so that neither of these two gfp genes is functional. However, if recombination occurs between the two gfp genes it will create a functional gfp protein. Cells containing such a functional recombinant gfp appear green under fluorescence microscopy. The rate of recombination between the two gfp sequences during a single round of replication is as high as 51%. Green cells appear during proliferation of a clonal clear-cell population and allow a small portion of these recombinations between sequences of proviral DNA to be detected. The frequency of recombination at the proviral DNA level is about 10(-5) events/cell division, which is very low compared with the frequency of recombination (51%) caused by reverse transcriptase and/or RNA polymerase II.
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PMID:Determination of the frequency of retroviral recombination between two identical sequences within a provirus. 1090 20

ELL (Eleven-nineteen Lysine rich Leukemia) is known to be an elongation factor resembling elongin for RNA polymerase II transcription. A homologue of human ELL (hELL) was identified in Drosophila melanogaster (dELL) and several cDNA clones were isolated from the embryonic cDNA library. We showed that dELL is expressed mainly in the ovaries and early embryonic stages by developmental Northern blot. dELL encodes a protein of 912 amino acids which is substantially longer than the hELL (612 aa). Immunostaining revealed that dELL was localized to nuclei in early embryos and to nuclei of nurse cells and follicle cells in the ovary suggesting its important role in early development of drosophila. To elucidate the function of this gene in drosophila, P-element mobilization was performed by utilizing a P-element inserted upstream of dELL. Southern analysis showed that isolated mutants are internal P-element deletions. These P-element deletions can now be used to isolate dELL mutations by EMS mutagenesis.
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PMID:dELL, a drosophila homologue of transcription elongation factor ELL (Eleven-nineteen Lysine rich Leukemia), is required for early development. 1197 8

Expression of human T-cell leukemia virus type 1 (HTLV-1) is regulated by the viral transcriptional activator Tax. Tax activates viral transcription through interaction with the cellular transcription factor CREB and the coactivators CBP/p300. One key property of the coactivators is the presence of histone acetyltransferase (HAT) activity, which enables p300/CBP to modify nucleosome structure. The data presented in this manuscript demonstrate that full-length p300 and CBP facilitate transcription of a reconstituted chromatin template in the presence of Tax and CREB. The ability of p300 and CBP to activate transcription from the chromatin template is dependent upon the HAT activity. Moreover, the coactivator HAT activity must be tethered to the template by Tax and CREB, since a p300 mutant that fails to interact with Tax did not facilitate transcription or acetylate histones. p300 acetylates histones H3 and H4 within nucleosomes located in the promoter and 5' proximal regions of the template. Nucleosome acetylation is accompanied by an increase in the level of binding of RNA polymerase II transcription factor TFIID and RNA polymerase II to the promoter. Interestingly, we found distinct transcriptional activities between CBP and p300. CBP, but not p300, possesses an N-terminal activation domain which directly activates Tax-mediated HTLV-1 transcription from a naked DNA template. Finally, using the chromatin immunoprecipitation assay, we provide the first direct experimental evidence that p300 and CBP are associated with the HTLV-1 long terminal repeat in vivo.
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PMID:Acetylation of nucleosomal histones by p300 facilitates transcription from tax-responsive human T-cell leukemia virus type 1 chromatin template. 1205 56

Retroviral recombination can occur between two viral RNA molecules (intermolecular) or between two sequences within the same RNA molecule (intramolecular). The rate of retroviral intramolecular recombination is high. Previous studies showed that, after a single round of replication, 50 to 60% of retroviral recombinations occur between two identical sequences within a Moloney murine leukemia virus-based vector. Recombination can occur at any polymerization step within the retroviral replication cycle. Although reverse transcriptase is assumed to contribute to the template switches, previous studies could not distinguish between changes introduced by host RNA polymerase II (Pol II) or by reverse transcriptase. A cell culture system has been established to detect the individual contribution of host RNA Pol II, host DNA polymerase or viral reverse transcriptase, as well as the recombination events taking place during minus-strand DNA synthesis and plus-strand DNA synthesis in a single round of viral intramolecular replication. Studies in this report demonstrate that intramolecular recombination between two identical sequences during transcription by host RNA Pol II is minimal and that most recombinations occur during minus-strand DNA synthesis catalyzed by viral reverse transcriptase.
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PMID:Intramolecular recombinations of Moloney murine leukemia virus occur during minus-strand DNA synthesis. 1220 40

The chromosomal features that influence retroviral integration site selection are not well understood. Here, we report the mapping of 226 avian sarcoma virus (ASV) integration sites in the human genome. The results show that the sites are distributed over all chromosomes, and no global bias for integration site selection was detected. However, RNA polymerase II transcription units (protein-encoding genes) appear to be favored targets of ASV integration. The integration frequency within genes is similar to that previously described for murine leukemia virus but distinct from the higher frequency observed with human immunodeficiency virus type 1. We found no evidence for preferred ASV integration sites over the length of genes and immediate flanking regions. Microarray analysis of uninfected HeLa cells revealed that the expression levels of ASV target genes were similar to the median level for all genes represented in the array. Although expressed genes were targets for integration, we found no preference for integration into highly expressed genes. Our results provide a more detailed description of the chromosomal features that may influence ASV integration and support the idea that distinct, virus-specific mechanisms mediate integration site selection. Such differences may be relevant to viral pathogenesis and provide utility in retroviral vector design.
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PMID:Genome-wide analyses of avian sarcoma virus integration sites. 1547 7

The mixed-lineage leukemia (MLL1/ALL-1/HRX) histone methyltransferase is involved in the epigenetic maintenance of transcriptional memory and the pathogenesis of human leukemias. To understand its role in cell type specification, we determined the human genomic binding sites of MLL1. We found that MLL1 functions as a human equivalent of yeast Set1. Like Set1, MLL1 localizes with RNA polymerase II (Pol II) to the 5' end of actively transcribed genes, where histone H3 lysine 4 trimethylation occurs. Consistent with this global role in transcription, MLL1 also localizes to microRNA (miRNA) loci that are involved in leukemia and hematopoiesis. In contrast to the 5' proximal binding behavior at most protein-coding genes, MLL1 occupies an extensive domain within a transcriptionally active region of the HoxA cluster. The ability of MLL1 to serve as a start site-specific global transcriptional regulator and to participate in larger chromatin domains at the Hox genes reveals dual roles for MLL1 in maintenance of cellular identity.
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PMID:Global and Hox-specific roles for the MLL1 methyltransferase. 1594 28


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