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)

Acute myeloid leukemia 1 (AML1) belongs to a family of DNA-binding proteins highly conserved through evolution. AML1 regulates the expression of several hematopoietic genes and is essential for murine fetal liver hematopoiesis. We report here that the histone methyltransferase SUV39H1, a mammalian ortholog of the Drosophila melanogaster SU(VAR) 3-9, forms complex with AML1. SUV39H1 methylates lysine 9 of the histone protein H3 leading to the formation of the high-affinity binding site on chromatin for proteins of the heterochromatin protein 1 family (HP1). The interaction of AML1 with SUV39H1 requires the N-terminus of AML1 where the Runt domain is located. Binding of AML1 to SUV39H1 abrogates the transactivating and DNA-binding properties of AML1 and dissociates the net-like nuclear structure of AML1. It has been reported that AML1 is capable of interaction with histone acetyl transferases (CBP, p300, and MOZ) and with component of the histone deacetylase complex (Sin3), and that the interaction with these coregulators affects the strength of AML1 in promoter regulation. Our data suggest that other enzymes are also involved in gene regulation by AML1 activity by modulating the affinity of AML1 for DNA.
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PMID:SUV39H1 interacts with AML1 and abrogates AML1 transactivity. AML1 is methylated in vivo. 1291 24

The multiplicity of transcription factors involved in hematologic malignancies suggests a complicated scenario in which many different molecular mechanisms lead to malignant transformation. We hypothesized that some of these proteins might physically and functionally interact and thus mechanistically link different diseases. The ETO protein of t(8;21) acute myeloid leukemia (AML) is an excellent candidate as a common factor because it is normally expressed in human hematopoietic cells, it binds to histone deacetylases (HDACs), and it interacts with the PLZF protein of t(11;17) acute promyelocytic leukemia. To determine whether ETO functionally links a broader range of disease entities, we asked whether ETO forms a complex with the Bcl-6 oncoprotein of B-cell lymphomas. We found that ETO and Bcl-6 are coexpressed in normal and malignant lymphoid tissue, where they interact and colocalize in nuclear speckles. ETO binds to the fourth zinc finger of Bcl-6, enhances Bcl-6 repression of artificial and endogenous genes in an HDAC-dependent manner, and forms a complex with Bcl-6 on the promoters of its endogenous target genes in B-cell lymphoma cells. Therefore, ETO is a bona fide corepressor that links the transcriptional pathogenesis of acute leukemias and B-cell lymphomas and offers a compelling target for transcriptional therapy of hematologic malignancies.
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PMID:ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein. 1455 Nov 42

The post-translational modification of the core histones is critical to the regulation of chromatin structure. Traditional methods for the determination of histone modification utilize immunoassay techniques to determine the extent and site of post-translational modification. These methods, though sensitive, require site-specific antibodies. This manuscript describes the application of reverse-phase high-pressure liquid chromatography and mass spectrometry (LC-MS) to analyze global modification levels of core histones. The method is fast, sensitive, and easily automated. Furthermore, the technique gives the global patterns of modification for all four core histones in a single experiment. The LC-MS method was optimized using histones extracted from bovine thymus. These methods were then applied to the characterization of changes in histone modification in acute myeloid leukemia (AML) cell lines treated with histone deacetylase (HDAC) inhibitors. Dose-dependent changes in the distribution of modified core histones were observed. These results were validated in primary leukemia cells from patients with refractory or relapsed AML or chronic lymphocytic leukemia (CLL) treated on a Phase I clinical trial of the HDAC inhibitor depsipeptide. An increase in the relative abundance of specific acetylated forms of histone H4 was readily observable in these patients at intervals of 4 and 24 h after treatment.
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PMID:Differential expression of histone post-translational modifications in acute myeloid and chronic lymphocytic leukemia determined by high-pressure liquid chromatography and mass spectrometry. 1469 58

Present studies demonstrate that treatment with the histone deacetylases inhibitor LAQ824, a cinnamic acid hydroxamate, increased the acetylation of histones H3 and H4, as well as induced p21(WAF1) in the human T-cell acute leukemia Jurkat, B lymphoblast SKW 6.4, and acute myelogenous leukemia HL-60 cells. This was associated with increased accumulation of the cells in the G(1) phase of the cell cycle, as well as accompanied by the processing and activity of caspase-9 and -3, and apoptosis. Exposure to LAQ824 increased the mRNA and protein expressions of the death receptors DR5 and/or DR4, but reduced the mRNA and protein levels of cellular FLICE-inhibitory protein (c-FLIP). As compared with treatment with Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or LAQ824 alone, pretreatment with LAQ824 increased the assembly of Fas-associated death domain and caspase-8, but not of c-FLIP, into the Apo-2L/TRAIL-induced death-inducing signaling complex. This increased the processing of caspase-8 and Bcl-2 interacting domain (BID), augmented cytosolic accumulation of the prodeath molecules cytochrome-c, Smac and Omi, as well as led to increased activity of caspase-3 and apoptosis. Treatment with LAQ824 also down-regulated the levels of Bcl-2, Bcl-x(L), XIAP, and survivin. Partial inhibition of apoptosis due to LAQ824 or Apo-2L/TRAIL exerted by Bcl-2 overexpression was reversed by cotreatment with LAQ824 and Apo-2L/TRAIL. Significantly, cotreatment with LAQ824 increased Apo-2L/TRAIL-induced apoptosis of primary acute myelogenous leukemia blast samples isolated from 10 patients with acute myelogenous leukemia. Taken together, these findings indicate that LAQ824 may have promising activity in augmenting Apo-2L/TRAIL-induced death-inducing signaling complex and apoptosis of human acute leukemia cells.
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PMID:Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. 1505 15

p300 and cyclic AMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a number of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematological disorders. p300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in critical protein domains, and these are often associated with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematological tumor formation. The involvement of these proteins in critical tumorigenic pathways (including TGF-beta, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.
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PMID:p300/CBP and cancer. 1515 77

Haploinsufficiency of the NSD1 gene is a hallmark of Sotos syndrome, and rearrangements of this gene by translocation can cause acute myeloid leukemia. The NSD1 gene product is a SET-domain histone lysine methyltransferase that has previously been shown to interact with nuclear receptors. We describe here a novel NSD1-interacting protein, Nizp1, that contains a SCAN box, a KRAB-A domain, and four consensus C2H2-type zinc fingers preceded by a unique finger derivative, referred to herein as the C2HR motif. The C2HR motif functions to mediate protein-protein interaction with the cysteine-rich (C5HCH) domain of NSD1 in a Zn(II)-dependent fashion, and when tethered to RNA polymerase II promoters, represses transcription in an NSD1-dependent manner. Mutations of the cysteine or histidine residues in the C2HR motif abolish the interaction of Nizp1 with NSD1 and compromise the ability of Nizp1 to repress transcription. Interestingly, converting the C2HR motif into a canonical C2H2 zinc finger has a similar effect. Thus, Nizp1 contains a novel type of zinc finger motif that functions as a docking site for NSD1 and is more than just a degenerate evolutionary remnant of a C2H2 motif.
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PMID:Nizp1, a novel multitype zinc finger protein that interacts with the NSD1 histone lysine methyltransferase through a unique C2HR motif. 1516 84

Recurrent cytogenetic abnormalities in leukemic blasts make these an attractive source for dendritic cells (DC) to induce a leukemia-specific immune response. In this study, three leukemic cell lines were investigated: Kasumi-1 and SKNO-1 (two acute myeloid leukemia (AML) cell lines carrying the (8;21)-chromosomal translocation, resulting in the expression of the leukemia-specific fusion protein AML1-eight-twenty-one) and REH, an acute lymphoblastic leukemia cell line with the (12;21)-chromosomal translocation and expression of translocation ETS-like leukemia-AML1. These fusion proteins are implicated in the pathogenesis of the leukemic state by recruiting corepressors and histone deacetylases (HDAC), which interfere with normal cell differentiation. In vitro generation of DC was achieved using a cytokine cocktail containing tumor necrosis factor alpha, granulocyte macrophage-colony stimulating factor, c-kit ligand, and soluble CD40 ligand; yet, addition of the HDAC inhibitor (Hdi) trichostatin A enhanced DC differentiation with retention of the fusion transcripts. These leukemic DC showed high-level CD83 and human leukocyte antigen (HLA)-DR expression and had a high allostimulatory potential. Only DC generated from these cell lines after Hdi induced blast-specific cytotoxic T cell responses in HLA-A-matched T cells with a cytotoxicity of 42% in parental Kasumi-1 and 83% in parental REH cells, respectively. This model system suggests that the Hdi supports the in vitro differentiation of DC from leukemic blasts with AML1-containing fusion proteins.
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PMID:Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins. 1519 37

The human telomerase reverse transcriptase (TERT) gene is transcriptionally inactivated in most differentiated cells but is reactivated in the majority of cancer cells. To elucidate how TERT is inactivated during differentiation, we applied all-trans retinoic acid (ATRA) to induce the differentiation of human teratocarcinoma (HT) cells and human acute myeloid leukemia (HL60) cells. We first showed that TERT promoter activity decreased rapidly, which preceded a gradual loss of endogenous telomerase activity following ATRA induction. To elucidate the underlying mechanisms of the reduced TERT promoter activity during differentiation, we performed epigenetic studies on the TERT promoter and found a progressive histone hypoacetylation coupled with a gradual accumulation of methylated cytosines in the TERT promoter. We also observed that the TERT promoter was less methylated in pluripotent HT cells than in multipotent HL60 cells throughout a 12-day differentiation process. This origin-dependent epigenetic change was also confirmed in histone acetylation studies, indicating that the TERT promoter was more resistant to deacetylation in HT cells than in HL60 cells. Taken together, our results demonstrate synergistic involvement of DNA methylation and histone deacetylation in the down-regulation of TERT promoter activity that may be dependent on the origin of the cell types, and they add new insight into the way telomerase activity may be regulated during differentiation.
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PMID:Epigenetic regulation of human telomerase reverse transcriptase promoter activity during cellular differentiation. 1523 14

Preclinical studies with the histone deacetylase (HDAC) inhibitor depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg/m(2) depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein, and 1D10 antigen expression. We conclude that depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with depsipeptide should examine alternative administration schedules.
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PMID:A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. 1546 34

DNA methylation provides a major epigenetic code (besides histone modification) of the lineage- and development-specific genes (such as regulators of differentiation in the hematopoietic lineages) that control expression of normal cells. However, DNA methylation is also involved in malignancies because aberrant methylating gene activity occurs during leukemic transformation. Thus, genes such as tumor suppressor genes, growth-regulatory genes, and adhesion molecules are often silenced in various hematopoietic malignancies by epigenetic inactivation via DNA hypermethylation. This inactivation is frequently seen not only in transformed cell lines but also in primary leukemia cells. Because this defect is amenable to reversion by pharmacologic means, agents that inhibit DNA methylation have been developed to specifically target this hypermethylation defect in leukemia and preleukemia cases. The most clinically advanced agents, the azanucleosides 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), were discovered more than 25 years ago, when their methylation-inhibitory activities, even at low concentrations, became apparent. Although both of these agents, like cytarabine, had been clinically used until then at high doses, the redevelopment of these agents for low-dose schedules has revealed very interesting clinical activities for treating myelodysplasia (MDS) and acute myeloid leukemia (AML). Because these diseases occur mostly in patients over 60 years of age, low-dose schedules with these compounds provide a very promising approach in such patient groups by virtue of their low nonhematologic toxicity profiles. In the present review, we describe the development of treatments that target DNA hypermethylation in MDS and AML, and clinical results are presented. In addition, pharmacologic DNA demethylation may be viewed as a platform for biological modification of malignant cells to become sensitized (or resensitized) to secondary signals, such as differentiating signals (retinoids, vitamin D3) and hormonal signals (eg, estrogen receptor in breast cancer cells, androgen receptor in prostate cancer cells). Finally, an in vitro synergism between the reactivating potency of demethylating agents and inhibitors of histone deacetylation has been tested in several pilot studies of AML and MDS treatment. Finally, gene reactivation by either group of compounds results in therapeutically meaningful reactivation of fetal hemoglobin in patients with severe hemoglobinopathies, extending the therapeutic range of derepressive epigenetic agents to nonmalignant hematopoietic disorders.
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PMID:DNA methylation as a therapeutic target in hematologic disorders: recent results in older patients with myelodysplasia and acute myeloid leukemia. 1548 40


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