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

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.
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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.
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PMID:Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. 981 5

Accumulating evidence points to a connection between cancer and transcriptional control by histone acetylation and deacetylation. This is particularly true with regard to the acute leukemias, many of which are caused by fusion proteins that have been created by chromosomal translocations. Genetic rearrangements that disrupt the retinoic acid receptor-alpha and acute myeloid leukemia-1 genes create fusion proteins that block terminal differentiation of hematopoietic cells by repressing transcription. These fusion proteins interact with nuclear hormone co-repressors, which recruit histone deacetylases to promoters to repress transcription. This finding suggests that proteins within the histone deacetylase complexes may be potential targets for pharmaceutical intervention in many leukemia patients.
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PMID:Role of histone deacetylases in acute leukemia. 989 71

Acute myeloid leukemia (AML) is still associated with a mortality of 60 to 80%. AML is characterized by a block in myeloid differentiation. The transcription factors PU.1 and C/EBPalpha are responsible for normal myeloid differentiation from stem cells to monocytes or granulocytes. In particular, PU.1 induces expression of the macrophage colony-stimulating factor (M-CSF) receptor and the development of monocytes, whereas C/EBPalpha increases the expression of the granulocyte colony-stimulating factor (G-CSF) receptor and leads to mature granulocytes. In AML, chromosomal aberrations result in oncoproteins such as AML1/ETO, PML/RARalpha, or activated Ras, which can deregulate genes important for normal myelopoiesis. Thus, AML1/ETO can bind to the transcription factor C/EBPalpha, inhibit C/EBPalpha-dependent transcription, and block granulocytic differentiation. However, AML1/ETO can also synergize with the transcription factor AML1 to enhance the activity of the M-CSF receptor promoter. On the other hand, the PML/RARalpha fusion protein causes transcriptional repression by recruiting the nuclear corepressor (N-CoR) histone deacetylase complex to the DNA, which results in decreased histone acetylation and a repressive chromatin organization. Here we describe methods to investigate whether and how signaling agonists induce myeloid differentiation and how oncoproteins might cause AML by modulating the activity of transcription factors that are pivotal for normal myeloid development.
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PMID:Analysis of the modulation of transcriptional activity in myelopoiesis and leukemogenesis. 1008 Sep 8

The t(8;21) between the AML1 and ETO genes is a commonly seen genetic alteration in acute myeloid leukemia. Recently, we reported that the fusion partner ETO binds to the human nuclear receptor co-repressor (NCOR), a member of the NCOR/SIN3/histone deacetylase complex. This complex mediates transcriptional repression as a result of chromatin remodeling. Here, we used a combination of fluorescence in situ hybridization and hybrid panels to localize the human NCOR gene (NCOR) to chromosome band 17p11.2. The position of human NCOR on 17p11 raises the possibility of deranged transcriptional regulation in malignant disorders associated with deletions of 17p.
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PMID:Nuclear receptor co-repressor gene localizes to 17p11.2, a frequently deleted band in malignant disorders. 1033 4

The (8;21) translocation, found in 12% of acute myeloid leukemia (AML), creates the chimeric fusion product, AML1-ETO. Previously, we demonstrated that the ETO moiety recruits a transcription repression complex that includes the histone deacetylase (HDAC1) enzyme. Here, we used inhibitors of HDAC1 to study the pathophysiology of AML1-ETO. Both the potent inhibitor, trichostatin (TSA), and the well-known but less specific inhibitor, phenylbutyrate (PB), could partially reverse ETO-mediated transcriptional repression. PB was also able to induce partial differentiation of the AML1-ETO cell line, Kasumi-1. With the intention of developing a clinically useful protocol, we combined PB with a number of other agents that induced differentiation and apoptosis of Kasumi-1 cells. In summary, transcriptional repression mediated by AML1-ETO appears to play a mechanistic role in the t(8;21) AML, and relief of repression using agents such as PB (alone or in combination) may prove to be therapeutically useful.
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PMID:Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. 1038 27

We investigated the effect of the histone deacetylase inhibitors (HDIs), trichostatin A and trapoxin A on leukemia cells and cell lines from the viewpoint of differentiation induction. TSA induced differentiation in erythroid cell lines by itself, whereas it synergistically enhanced the differentiation that was directed by all-trans retinoic acid (ATRA) or vitamin D3 in U937, HL60 and NB4 cells. The combined treatment of HDI with ATRA induced differentiation in ATRA-resistant HL60 and NB4 cells. The transcriptional expression during the treatment with HDI was examined in HL60, U937 and MEG-O1. Cell cycle-regulator genes (p21waf1 and p16INK4A) were upregulated or constantly expressed, erythroid-specific genes (GATA-1, beta-globin) were silent or downregulated, and housekeeping genes (beta-actin and GAPDH) were constantly expressed. Twelve of 35 (34%) clinical samples from AML patients ranging from M0 to M7 also displayed both phenotypical and morphological changes by the treatment with TSA alone. HDIs are thus the potent inducer or enhancer of differentiation in acute myeloid leukemia and regulate transcription in an ordered manner.
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PMID:Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy. 1048 80

The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1-ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor alpha in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.
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PMID:The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein. 1068 54

The role of fusion proteins in acute myeloid leukemia (AML) is well recognized, but the leukemic target cell and the cellular mechanisms generating the AML phenotype are essentially unknown. To address this issue, an in vitro model to study the biologic activity of leukemogenic proteins was established. Highly purified human hematopoietic progenitor cells/stem cells (HPC/HSC) in bulk cells or single cells are transduced with retroviral vectors carrying cDNA of the fusion protein and the green fluorescent protein (GFP), purified to homogeneity and induced into multilineage or unilineage differentiation by specific hematopoietic growth factor (HGF) combinations. Expression of PML/RAR alpha fusion protein in human HPC/HSC dictates the acute promyelocytic leukemia (APL) phenotype, largely through these previously unreported effects: rapid induction of HPC/HSC differentiation to the promyelocytic stage, followed by maturation arrest, which is abolished by retinoic acid; reprogramming of HPC commitment to preferential granulopoietic differentiation, irrespective of the HGF stimulus (transduction of single sibling HPC formally demonstrated this effect); HPC protection from apoptosis induced by HGF deprivation. A PML/RAR alpha mutated in the co-repressor N-CoR/histone deacetylase binding region lost these biologic effects, showing that PML/RAR alpha alters the early hematopoietic program through N-CoR-dependent target gene repression mechanisms. These observations identify the cellular mechanism underlying development of the APL phenotype, showing that the fusion protein directly dictates the specific lineage and differentiation stage of leukemic cells. (Blood. 2000;96:1531-1537)
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PMID:PML/RAR alpha fusion protein expression in normal human hematopoietic progenitors dictates myeloid commitment and the promyelocytic phenotype. 1094 2

Few chemotherapy agents have demonstrated activity in patients with myelodysplastic syndromes (MDS) and supportive management remains the standard of care. An increasing number of new drugs in development are being directed at specific molecular or biological targets of these diseases. Topotecan, a topoisomerase I inhibitor, has shown single-agent activity and is now being combined with other agents, including cytarabine. The aminothiol amifostine induces responses in about 30% of patients; however, its role is still being clarified. Agents that inhibit histone deacetylase and target DNA hypermethylation, thus permitting derepression of normal genes, include 5-azacytidine, decitabine, phenylbutyrate, and depsipeptide. Arsenic trioxide has demonstrated impressive activity in acute promyelocytic leukemia and preclinical data suggest the potential for activity in MDS. UCN-01 is a novel agent that inhibits protein kinase C and other protein kinases important for progression through the G1 and G2 phases of the cell cycle. Dolastatin-10 has extremely potent in vitro activity against a variety of tumor cell lines. Since its dose-limiting toxicities include myelosuppression, it is being studied in acute myelogenous leukemia (AML) and MDS. Ras may play a role in MDS, and activation of this gene and its signaling pathways may require farnesylation. Several farnesyl transferase inhibitors are now available for study in patients with MDS. An increasing body of data suggests a possible role for angiogenesis in MDS, and several antiangiogenesis agents are in clinical trials, including thalidomide, SU5416, and anti-vascular endothelial growth factor (VEGF) antibodies. Development of new drugs and regimens will be facilitated by recently developed standardized response criteria. Future clinical trials should focus on rational combinations of these agents and others with the goal of curing patients with MDS.
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PMID:Novel therapeutic agents for the treatment of myelodysplastic syndromes. 1104 23


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