Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 19

Publication Record

Connections

High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML.
Zhao Y, Liu Q, Acharya P, Stengel KR, Sheng Q, Zhou X, Kwak H, Fischer MA, Bradner JE, Strickland SA, Mohan SR, Savona MR, Venters BJ, Zhou MM, Lis JT, Hiebert SW
(2016) Cell Rep 16: 2003-16
MeSH Terms: Antineoplastic Agents, Azepines, Cell Line, Tumor, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Clustered Regularly Interspaced Short Palindromic Repeats, DNA-Directed RNA Polymerases, Drug Resistance, Neoplasm, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute, MicroRNAs, Multigene Family, Myeloid Cell Leukemia Sequence 1 Protein, Promoter Regions, Genetic, Protein Isoforms, Proteins, Proto-Oncogene Proteins c-kit, Transcription, Genetic, Translocation, Genetic, Triazoles
Show Abstract · Added April 6, 2017
Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
23 MeSH Terms
Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein.
Yang G, Thompson MA, Brandt SJ, Hiebert SW
(2007) Oncogene 26: 91-101
MeSH Terms: Cell Line, Tumor, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Enzyme Inhibitors, Histone Deacetylase Inhibitors, Humans, Hydrolysis, Immunoprecipitation, Proto-Oncogene Proteins, RUNX1 Translocation Partner 1 Protein, Transcription Factors, Translocation, Genetic
Show Abstract · Added March 5, 2014
The t(8;21) chromosomal translocation that generates the fusion oncoprotein RUNX1-ETO predominates in leukemia patients of the French-American-British (FAB) class M2 subtype. The oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations. Here, we show that RUNX1-ETO undergoes degradation in response to treatment with histone deacetylase inhibitors, one of which, depsipeptide (DEP), is currently undergoing phase II clinical testing in a variety of malignancies. These compounds induce turnover of RUNX1-ETO without affecting the stability of RUNX1-ETO partner proteins. In addition, RUNX1-ETO physically interacts with heat shock protein 90 (HSP90). DEP treatment interrupts the association of RUNX1-ETO with HSP90 and induces proteasomal degradation of RUNX1-ETO. DEP and the HSP90 antagonist 17-allylamino-geldanamycin (17-AAG) both triggered RUNX1-ETO degradation, but without any additive or cooperative effects. These findings may stimulate the development of more rational and effective approaches for treating t(8;21) patients using histone deacetylase inhibitors or HSP90 inhibitors.
0 Communities
3 Members
0 Resources
14 MeSH Terms
Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein.
Yang G, Khalaf W, van de Locht L, Jansen JH, Gao M, Thompson MA, van der Reijden BA, Gutmann DH, Delwel R, Clapp DW, Hiebert SW
(2005) Mol Cell Biol 25: 5869-79
MeSH Terms: Animals, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Down-Regulation, Genes, Reporter, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Leukemia, Myeloid, Acute, Mice, Neurofibromatosis 1, Neurofibromin 1, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Proto-Oncogene Proteins, RUNX1 Translocation Partner 1 Protein, Repressor Proteins, Transcription Factors, Transcription, Genetic, Translocation, Genetic
Show Abstract · Added March 5, 2014
Von Recklinghausen's disease is a relatively common familial genetic disorder characterized by inactivating mutations of the Neurofibromatosis-1 (NF1) gene that predisposes these patients to malignancies, including an increased risk for juvenile myelomonocytic leukemia. However, NF1 mutations are not common in acute myeloid leukemia (AML). Given that the RUNX1 transcription factor is the most common target for chromosomal translocations in acute leukemia, we asked if NF1 might be regulated by RUNX1. In reporter assays, RUNX1 activated the NF1 promoter and cooperated with C/EBPalpha and ETS2 to activate the NF1 promoter over 80-fold. Moreover, the t(8;21) fusion protein RUNX1-MTG8 (R/M), which represses RUNX1-regulated genes, actively repressed the NF1 promoter. R/M associated with the NF1 promoter in vivo and repressed endogenous NF1 gene expression. In addition, similar to loss of NF1, R/M expression enhanced the sensitivity of primary myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor. Our results indicate that the NF1 tumor suppressor gene is a direct transcriptional target of RUNX1 and the t(8;21) fusion protein, suggesting that suppression of NF1 expression contributes to the molecular pathogenesis of AML.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins.
Barseguian K, Lutterbach B, Hiebert SW, Nickerson J, Lian JB, Stein JL, van Wijnen AJ, Stein GS
(2002) Proc Natl Acad Sci U S A 99: 15434-9
MeSH Terms: Binding Sites, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit, DNA, Neoplasm, DNA-Binding Proteins, Humans, Hydrophobic and Hydrophilic Interactions, Leukemia, Myeloid, Acute, Microscopy, Fluorescence, Oncogene Proteins, Fusion, Protein Sorting Signals, Protein Structure, Tertiary, Protein Transport, Proto-Oncogene Proteins, RUNX1 Translocation Partner 1 Protein, Recombinant Fusion Proteins, Repressor Proteins, Structure-Activity Relationship, Subcellular Fractions, Transcription Factors, Transfection, Translocation, Genetic, Tumor Cells, Cultured, Zinc Fingers
Show Abstract · Added June 10, 2010
Leukemic disease can be linked to aberrant gene expression. This often is the result of molecular alterations in transcription factors that lead to their misrouting within the nucleus. The acute myelogenous leukemia-related fusion protein AML1ETO is a striking example. It originates from a gene rearrangement t(8;21) that fuses the N-terminal part of the key hematopoietic regulatory factor AML1 (RUNX1) to the ETO (MTG8) repressor protein. AML1ETO lacks the intranuclear targeting signal of the wild-type AML1 and is directed by the ETO component to alternate nuclear matrix-associated sites. To understand this aberrant subnuclear trafficking of AML1ETO, we created a series of mutations in the ETO protein. These were characterized biochemically by immunoblotting and in situ by immunofluorescence microscopy. We identified two independent subnuclear targeting signals in the N- and C-terminal regions of ETO that together direct ETO to the same binding sites occupied by AML1ETO. However, each segment alone is targeted to a different intranuclear location. The N-terminal segment contains a nuclear localization signal and the conserved hydrophobic heptad repeat domain responsible for protein dimerization and interaction with the mSin3A transcriptional repressor. The C-terminal segment spans the nervy domain and the zinc finger region, which together support interactions with the corepressors N-CoR and HDACs. Our findings provide a molecular basis for aberrant subnuclear targeting of the AML1ETO protein, which is a principal defect in t(8;21)-related acute myelogenous leukemia.
1 Communities
1 Members
0 Resources
25 MeSH Terms
The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia.
Linggi B, Müller-Tidow C, van de Locht L, Hu M, Nip J, Serve H, Berdel WE, van der Reijden B, Quelle DE, Rowley JD, Cleveland J, Jansen JH, Pandolfi PP, Hiebert SW
(2002) Nat Med 8: 743-50
MeSH Terms: Antigens, CD, CD4 Antigens, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit, Gene Expression Regulation, Neoplastic, Genes, Reporter, Genes, Tumor Suppressor, Hematopoietic Stem Cells, Humans, K562 Cells, Leukemia, Myeloid, Acute, Oncogene Proteins, Fusion, Plasmids, RUNX1 Translocation Partner 1 Protein, Repressor Proteins, Transcription Factors, Transcription, Genetic, Translocation, Genetic, Tumor Cells, Cultured, Tumor Suppressor Protein p14ARF
Show Abstract · Added June 10, 2010
The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. This translocation creates a fusion protein consisting of the acute myeloid leukemia-1 transcription factor and the eight-twenty-one corepressor (AML1 ETO), which represses transcription through AML1 (RUNX1) DNA binding sites and immortalizes hematopoietic progenitor cells. We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. AML1 ETO repressed the p14(ARF) promoter and reduced endogenous levels of p14(ARF) expression in multiple cell types. In contrast, AML1 stimulated p14(ARF) expression and induced phenotypes consistent with cellular senescence. Chromatin immunoprecipitation assays demonstrated that AML1 ETO was specifically bound to the p14(ARF) promoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14(ARF) mRNA were markedly lower when compared with other acute myeloid leukemias lacking this translocation. Repression of p14(ARF) may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14(ARF) is an important tumor suppressor in a large number of human leukemias.
1 Communities
1 Members
0 Resources
21 MeSH Terms
The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein.
Melnick AM, Westendorf JJ, Polinger A, Carlile GW, Arai S, Ball HJ, Lutterbach B, Hiebert SW, Licht JD
(2000) Mol Cell Biol 20: 2075-86
MeSH Terms: Acute Disease, Animals, COS Cells, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors, Leukemia, Myeloid, Promyelocytic Leukemia Zinc Finger Protein, Proto-Oncogene Proteins, RUNX1 Translocation Partner 1 Protein, Transcription Factors, Transfection, Translocation, Genetic, Zinc Fingers
Show Abstract · Added June 10, 2010
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.
1 Communities
1 Members
0 Resources
17 MeSH Terms
Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein.
Fenrick R, Amann JM, Lutterbach B, Wang L, Westendorf JJ, Downing JR, Hiebert SW
(1999) Mol Cell Biol 19: 6566-74
MeSH Terms: Burkitt Lymphoma, Child, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 21, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Humans, Models, Genetic, Neoplasm Proteins, Oncogene Proteins, Fusion, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ets, RUNX1 Translocation Partner 1 Protein, Repressor Proteins, Sin3 Histone Deacetylase and Corepressor Complex, Transcription Factors, Translocation, Genetic
Show Abstract · Added June 10, 2010
t(12;21) is the most frequent translocation found in pediatric B-cell acute lymphoblastic leukemias. This translocation fuses a putative repressor domain from the TEL DNA-binding protein to nearly all of the AML-1B transcription factor. Here, we demonstrate that fusion of the TEL pointed domain to the GAL4 DNA-binding domain resulted in sequence-specific transcriptional repression, indicating that the pointed domain is a portable repression motif. The TEL pointed domain functioned equally well when the GAL4 DNA-binding sites were moved 600 bp from the promoter, suggesting an active mechanism of repression. This lead us to demonstrate that wild-type TEL and the t(12;21) fusion protein bind the mSin3A corepressor. In the fusion protein, both TEL and AML-1B contribute mSin3 interaction domains. Deletion mutagenesis indicated that both the TEL and AML-1B mSin3-binding domains contribute to repression by the fusion protein. While both TEL and AML-1B associate with mSin3A, TEL/AML-1B appears to bind this corepressor much more stably than either wild-type protein, suggesting a mode of action for the t(12;21) fusion protein.
1 Communities
1 Members
0 Resources
19 MeSH Terms
ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors.
Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Davie JR, Huynh KD, Bardwell VJ, Lavinsky RM, Rosenfeld MG, Glass C, Seto E, Hiebert SW
(1998) Mol Cell Biol 18: 7176-84
MeSH Terms: Cell Line, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Histone Deacetylases, Humans, Leukemia, Myeloid, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Precipitin Tests, Proto-Oncogene Proteins, RUNX1 Translocation Partner 1 Protein, Recombinant Fusion Proteins, Repressor Proteins, Saccharomyces cerevisiae Proteins, Transcription Factors, Translocation, Genetic
Show Abstract · Added June 10, 2010
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.
1 Communities
1 Members
0 Resources
18 MeSH Terms
The MYND motif is required for repression of basal transcription from the multidrug resistance 1 promoter by the t(8;21) fusion protein.
Lutterbach B, Sun D, Schuetz J, Hiebert SW
(1998) Mol Cell Biol 18: 3604-11
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Dimerization, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Myeloid, Neoplasm Proteins, Oncogene Proteins, Fusion, Point Mutation, Promoter Regions, Genetic, Proto-Oncogene Protein c-ets-1, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ets, RUNX1 Translocation Partner 1 Protein, Recombinant Fusion Proteins, Repressor Proteins, Structure-Activity Relationship, Transcription Factors, Translocation, Genetic, Tumor Cells, Cultured, Zinc Fingers
Show Abstract · Added June 10, 2010
Chromosomal translocations in acute leukemia that affect the AML-1/CBFbeta transcription factor complex create dominant inhibitory proteins. However, the mechanisms by which these proteins act remain obscure. Here we demonstrate that the multidrug resistance 1 (MDR-1) promoter is a target for AML/ETO transcriptional repression. This repression is of basal, not activated, expression from the MDR-1 promoter and thus represents a new mechanism for AML/ETO function. We have defined two domains in AML/ETO that are required for repression of basal transcription from the MDR-1 promoter: a hydrophobic heptad repeat (HHR) motif and a conserved zinc finger (ZnF) domain termed the MYND domain. The HHR mediates formation of AML/ETO homodimers and AML/ETO-ETO heterodimers. Single serine substitutions at conserved cysteine residues within the predicted ZnFs also abrogate transcriptional repression. Finally, we observe that AML/ETO can also inhibit Ets-1 activation of the MDR-1 promoter, indicating that AML/ETO can disrupt both basal and Ets-1-dependent transcription. The fortuitous inhibition of MDR-1 expression in t(8;21)-containing leukemias may contribute to the favorable response of these patients to chemotherapeutic drugs.
1 Communities
1 Members
0 Resources
24 MeSH Terms
DNA copy number changes in alveolar soft part sarcoma: a comparative genomic hybridization study.
Kiuru-Kuhlefelt S, El-Rifai W, Sarlomo-Rikala M, Knuutila S, Miettinen M
(1998) Mod Pathol 11: 227-31
MeSH Terms: Adolescent, Adult, Aged, Child, Chromosome Aberrations, Chromosome Disorders, Chromosome Mapping, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 16, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 8, Chromosomes, Human, Pair 9, DNA, Neoplasm, Female, Gene Amplification, Gene Deletion, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Nucleic Acid Hybridization, Sarcoma, Alveolar Soft Part, X Chromosome
Show Abstract · Added March 5, 2014
Alveolar soft part sarcoma (ASPS) is a rare, histologically distinctive soft tissue sarcoma typically occurring in children and young adults. Although the tumor often shows focal expression of muscle markers, its relationship with rhabdomyosarcoma is not established. The genetic background of ASPS is poorly understood. This study was undertaken to analyze the DNA copy number changes in 13 cases of ASPS using comparative genomic hybridization (CGH) on formaldehyde-fixed, paraffin-embedded tissue sections. Four ASPS cases showed DNA copy number changes. Gains were more common than losses. Gains observed in more than one case included 1q, 8q, 12q and 16p. Although these findings do not show consistent DNA copy number changes in ASPS, they give preliminary clues to genomic areas that might be important in the pathogenesis of ASPS.
0 Communities
1 Members
0 Resources
26 MeSH Terms