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)

Evidence from clinical and laboratory studies suggests that angiogenesis is important in the progression of solid tumours and hematologic malignancies. We have shown that the naturally occurring tetrapeptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a potent angiogenic factor normally present at nanomolar concentrations in the blood. A murine leukemia model was used to assess whether there was a correlation between levels of endogenous AcSDKP and the development of disease. Levels of AcSDKP in the plasma and bone marrow (BM) cells from mice bearing an acute myeloid leukemia (AML) were five- to ten-fold greater than those in non-leukemic mice. Furthermore, a strong correlation between the concentration of endogenous AcSDKP and the progression of AML was demonstrated. These results are consistent with the marked increase in BM vascularity observed in leukemic mice. The physiologic relevance of these findings awaits further studies and the contribution of AcSDKP to the pathogenesis of leukemia is under investigation.
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PMID:Evidence for an association of high levels of endogenous Acetyl-Ser-Asp-Lys-Pro, a potent mediator of angiogenesis, with acute myeloid leukemia development. 1706 80

Seven of 11 patients with acute myeloblastic leukemia (AML) had allele(s) in which more than half of 27 CpG sites in the p15 gene were methylated. The p15 CpG island region was surrounded with both the acetylated histone H3 (AcH3) and dimethylated histone H3-lysine 9 (MeH3K9) in bone marrow cells of AML patients, whereas with AcH3 alone in normal marrow cells. The p15 CpG islands of DNA immunoprecipitated with anti-AcH3 antibody and anti-MeH3K9 antibody were not always unmethylated and methylated, respectively, in the patients. These results suggest perturbed modifications of histone H3 around the p15 CpG island region in AML.
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PMID:Analysis of histone modification around the CpG island region of the p15 gene in acute myeloblastic leukemia. 1707 88

Human enhancer of zeste 2 (EZH2) protein belongs to the multiprotein polycomb repressive complex 2, which also includes suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). The polycomb repressive complex 2 complex possesses histone methyltransferase activity mediated by the Su(var)3-9, enhancer of zeste, and trithorax domain of EZH2, which methylates histone H3 on lysine (K)-27 (H3K27). In the present studies, we determined that treatment with the hydroxamate histone deacetylase inhibitor LBH589 or LAQ824 depleted the protein levels of EZH2, SUZ12, and EED in the cultured (K562, U937, and HL-60) and primary human acute leukemia cells. This was associated with decreased levels of trimethylated and dimethylated H3K27, with concomitant depletion of the homeobox domain containing HOXA9 and of MEIS1 transcription factors. Knockdown of EZH2 by EZH2 small interfering RNA also depleted SUZ12 and EED, inhibited histone methyltransferase activity, and reduced trimethylated and dimethylated H3K27 levels, with a concomitant loss of clonogenic survival of the cultured acute myelogenous leukemia (AML) cells. EZH2 small interfering RNA sensitized the AML cells to LBH589-mediated depletion of EZH2, SUZ12, and EED; loss of clonogenic survival; and LBH589-induced differentiation of the AML cells. These findings support the rationale to test anti-EZH2 treatment combined with hydroxamate histone deacetylase inhibitors as an antileukemia epigenetic therapy, especially against AML with coexpression of EZH2, HOXA9, and MEIS1 genes.
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PMID:Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells. 1717 12

Disrupted patterns of acetylation and deacetylation of core histones play an important role in silencing transcription of hematopoietic important genes in acute myeloid leukemia (AML). A thorough investigation of these mechanisms and the response to pharmacologic modifiers will provide a better understanding of the role of histone acetylation in leukemogenesis. We describe here an analytical approach that combines acid urea polyacrylamide gel electrophoresis (AU-PAGE), amino acid coded mass tagging (AACM), and mass spectrometry (MS) for the investigation of histone acetylation patterns. The combined approach was used to follow the dynamics of H4 acetylation in Kasumi-1 cells harboring the fusion gene AML1/ETO shown to aberrantly recruit histone deacetylases (HDACs). The histones in Kasumi-1 cells were labeled by growing the cells in media in which lysine was replaced with stable isotope-labeled lysine (Lys-D4). Labeled and unlabeled cells were treated with depsipeptide and analyzed at different time points (0, 4, 8, 12, 24, and 48 h). The cells were mixed, the histone was extracted, and acetylated H4 isoforms were separated using AU-PAGE before in-gel trypsin digestion. The digests were analyzed by MALDI-TOF MS. Peptides were identified by mass and isotope pattern. LC-MS/MS of Arg-C digests were also performed to verify the acetylation pattern for H4. The major pattern of acetylation was determined as follows: initial acetylation at K16, followed by acetylation at K12, and finally acetylation of either K8 and/or K5.
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PMID:Histone H4 N-terminal acetylation in Kasumi-1 cells treated with depsipeptide determined by acetic acid-urea polyacrylamide gel electrophoresis, amino acid coded mass tagging, and mass spectrometry. 1720 51

Pleiomorphic adenoma gene (PLAG) family proteins are oncogenes involved in various malignancies including lipoblastomas, hepatoblastomas, and acute myeloid leukemia. Overexpression of PLAGL2 induces cell transformation and proliferation, but little is known about how its activities are regulated. We previously showed that transcriptional activity of PLAGL2 is negatively regulated by sumoylation. Here we report that Tip60 modulates PLAGL2 functions through acetylation. Tip60 associates with PLAGL2 through its zinc finger domain and acetylates PLAGL2. Wild-type but not the histone acetyltransferase (HAT)-minus mutant form of Tip60 enhances PLAGL2-mediated transactivation. In addition, coexpression of Tip60 and PLAGL2 completely abolishes the sumoylation of PLAGL2. Both Tip60 and DN-Ubc9 increase transactivation activity of wild-type but not the sumoylation deficient form of PLAGL2 (K250, 269, 356R), indicating that Tip60 acetylates PLAGL2 and abolishes the sumoylation of PLAGL2 possibly through modification of the same lysine residues (K250, 269, 356) within PLAGL2. Tip60 effects vary between different PLAGL2 target gene promoters, suggesting that Tip60 is a novel promoter-specific coactivator of PLAGL2. This is the first demonstration that Tip60 can function as a sumoylation inhibitor in part through its intrinsic acetyltransferase activity to regulate specific gene expression.
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PMID:Tip60 modulates PLAGL2-mediated transactivation by acetylation. 1755 69

Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus.
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PMID:NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. 1758 99

The retinoic acid receptor (RAR) alpha gene (RARA) encodes 2 major isoforms and mediates positive effects of all-trans retinoic acid (ATRA) on myelomonocytic differentiation. Expression of the ATRA-inducible (RARalpha2) isoform increases with myelomonocytic differentiation and appears to be down-regulated in many acute myeloid leukemia (AML) cell lines. Here, we demonstrate that relative to normal myeloid stem/progenitor cells, RARalpha2 expression is dramatically reduced in primary AML blasts. Expression of the RARalpha1 isoform is also significantly reduced in primary AML cells, but not in AML cell lines. Although the promoters directing expression of RARalpha1 and RARalpha2 are respectively unmethylated and methylated in AML cell lines, these regulatory regions are unmethylated in all the AML patient cell samples analyzed. Moreover, in primary AML cells, histones associated with the RARalpha2 promoter possessed diminished levels of H3 acetylation and lysine 4 methylation. These results underscore the complexities of the mechanisms responsible for deregulation of gene expression in AML and support the notion that diminished RARA expression contributes to leukemogenesis.
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PMID:DNA methylation-independent loss of RARA gene expression in acute myeloid leukemia. 1799 18

The molecular heterogeneity of acute leukemias and other tumors constitutes a major obstacle towards understanding disease pathogenesis and developing new targeted-therapies. Aberrant gene regulation is a hallmark of cancer and plays a central role in determining tumor phenotype. We predicted that integration of different genome-wide epigenetic regulatory marks along with gene expression levels would provide greater power in capturing biological differences between leukemia subtypes. Gene expression, cytosine methylation and histone H3 lysine 9 (H3K9) acetylation were measured using high-density oligonucleotide microarrays in primary human acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) specimens. We found that DNA methylation and H3K9 acetylation distinguished these leukemias of distinct cell lineage, as expected, but that an integrative analysis combining the information from each platform revealed hundreds of additional differentially expressed genes that were missed by gene expression arrays alone. This integrated analysis also enhanced the detection and statistical significance of biological pathways dysregulated in AML and ALL. Integrative epigenomic studies are thus feasible using clinical samples and provide superior detection of aberrant transcriptional programming than single-platform microarray studies.
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PMID:An integrative genomic and epigenomic approach for the study of transcriptional regulation. 1836 23

CCAAT enhancer binding protein alpha (C/EBP alpha) is the founding member of a family of basic region/leucine zipper (bZIP) transcription factors and is a master regulator of granulopoiesis. It is expressed at high levels throughout myeloid differentiation and binds to the promoters of multiple myeloid-specific genes at different stages of myeloid maturation. Profound hematopoietic abnormalities occur in mice nullizygous for C/EBP alpha including a selective early block in the differentiation of granulocytes. Mutations in C/EBP alpha are present in a subset of patients with AML presenting with a normal karyotype. These mutations can result in the expression of a 30 kDa dominant negative C/EBP alpha isoform, which contributes to loss of C/EBP alpha function. The molecular basis for this observation remains unknown. In addition to phosphorylation, C/EBP alpha is modified, post-translationally by a small ubiquitin-related modifier (SUMO) at a lysine residue (K159), which lies within the growth inhibitory region of the C/EBP alpha protein. Sumoylation at K159 in the C/EBP alpha protein prevents association of the SWI/SNF chromatin remodeling complex with C/EBP alpha, thereby hampering transactivation. In this review, the functional implications of post-translational modification, particularly sumoylation, of C/EBP alpha in normal granulopoiesis and leukemia are considered.
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PMID:Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBP alpha). 1840 80

Mutations affecting NPM1 (nucleophosmin) are the most common genetic lesions found in acute myeloid leukemia (AML). NPM1 is one of the most abundant proteins found in the nucleolus and has links to the MDM2/p53 tumor suppressor pathway. A distinctive feature of NPM1 mutants in AML is their aberrant localization to the cytoplasm of leukemic cells. This mutant phenotype is the result of the substitution of several C-terminal residues, including one or two conserved tryptophan residues, with a leucine-rich nuclear export signal. The exact molecular mechanism underlying the loss of nucleolar retention, and the role of the tryptophans, remains unknown. In this study we have determined the structure of an independently folded globular domain in the C terminus of NPM1 using NMR spectroscopy, and we report that the conserved tryptophans are critical for structure. This domain is necessary for the nucleolar targeting of NPM1 and is disrupted by mutations in AML with cytoplasmic NPM1. Furthermore, we identify conserved surface-exposed lysine residues that are functionally rather than structurally important for nucleolar localization. This study provides new focus for efforts to understand the pathogenesis of AML with cytoplasmic NPM1 and may be used to aid the design of small molecules that target the C-terminal domain of NPM1 to act as novel anti-proliferative and anti-leukemia therapeutics.
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PMID:Structural consequences of nucleophosmin mutations in acute myeloid leukemia. 1851 15


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