Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia–associated TEL-AML1 oncoprotein

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2557-2561 ◽  
Author(s):  
Fabien Guidez ◽  
Kevin Petrie ◽  
Anthony M. Ford ◽  
Huafeng Lu ◽  
Caroline A. Bennett ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Repression ◽  
Childhood Leukemia ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Chimeric Protein ◽  
Chromosomal Translocation ◽  
Corepressor Complex ◽  
Nuclear Receptor Corepressor ◽  
Frame Fusion

Abstract The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in a pediatric cancer and occurs in approximately 25% of common acute lymphoblastic leukemia (cALL) cases. This rearrangement results in the in frame fusion of the 5′-region of the ETS-related gene, TEL(ETV6), to almost the entire acute myeloid leukemia 1 (AML1) (also called CBFA2 orPEBP2AB1) locus and expression of the TEL-AML1 chimeric protein. Although AML1 stimulates transcription, TEL-AML1 functions as a repressor of some AML1 target genes. In contrast to the wild type AML1 protein, both TEL and TEL-AML1 interact with N-CoR, a component of the nuclear receptor corepressor complex with histone deacetylase activity. The interaction between TEL and N-CoR requires the central region of TEL, which is retained in TEL-AML1, and TEL lacking this domain is impaired in transcriptional repression. Taken together, our results suggest that TEL-AML1 may contribute to leukemogenesis by recruiting N-CoR to AML1 target genes and thus imposing an altered pattern of their expression.

Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia–associated TEL-AML1 oncoprotein

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2557-2561 ◽  
Author(s):  
Fabien Guidez ◽  
Kevin Petrie ◽  
Anthony M. Ford ◽  
Huafeng Lu ◽  
Caroline A. Bennett ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Repression ◽  
Childhood Leukemia ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Chimeric Protein ◽  
Chromosomal Translocation ◽  
Corepressor Complex ◽  
Nuclear Receptor Corepressor ◽  
Frame Fusion

The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in a pediatric cancer and occurs in approximately 25% of common acute lymphoblastic leukemia (cALL) cases. This rearrangement results in the in frame fusion of the 5′-region of the ETS-related gene, TEL(ETV6), to almost the entire acute myeloid leukemia 1 (AML1) (also called CBFA2 orPEBP2AB1) locus and expression of the TEL-AML1 chimeric protein. Although AML1 stimulates transcription, TEL-AML1 functions as a repressor of some AML1 target genes. In contrast to the wild type AML1 protein, both TEL and TEL-AML1 interact with N-CoR, a component of the nuclear receptor corepressor complex with histone deacetylase activity. The interaction between TEL and N-CoR requires the central region of TEL, which is retained in TEL-AML1, and TEL lacking this domain is impaired in transcriptional repression. Taken together, our results suggest that TEL-AML1 may contribute to leukemogenesis by recruiting N-CoR to AML1 target genes and thus imposing an altered pattern of their expression.

E2a-Pbx1 Direct Targets and Secondary Mutations in Leukemogenesis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3343-3343
Author(s):  
Christofer Diakos ◽  
Yuanyuan Xiao ◽  
Jerry Hofmann ◽  
Shichun Zheng ◽  
Michelle Kang ◽  
...  
Keyword(s):  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Gene Promoter ◽  
Transactivation Domain ◽  
Oncogenic Potential ◽  
Expression Arrays ◽  
Functional Regulation ◽  
Copy Number Changes

Abstract E2a-Pbx1 is expressed as a result of the t(1;19) chromosomal translocation in nearly 5% of cases of acute lymphoblastic leukemia. The E2a-Pbx1 chimeric transcription factor contains the N-terminal transactivation domain of E2A fused to the C-terminal DNAbinding homeodomain of Pbx1. Previews studies indicate that additional genetic events may be required for E2A-Pbx1-leukemic transformation, based on long incubation times and monoclonal nature of tumors observed in mouse models. While there is no doubt of its oncogenic potential, the mechanisms of E2a-Pbx1-mediated pre-B cell transformation and the nature of direct E2a-Pbx1 target genes and additional events that complement the fusion oncogene to create full-blown leukemia are still unclear. Herein we used chromatin immunoprecipitation (ChIP-chip) assays to identify direct targets of E2a-Pbx1, and we used gene and miRNA expression arrays of siRNA E2a-Pbx1-silenced cells to evaluate changes in expression induced by the fusion protein. To identify complementary genetic rearrangements, analyses of primary E2a-Pbx1 leukemias were performed to copy number changes and loss of heterozygosity which might identify mutations that synergize with the direct/functional E2a-Pbx1 targets to produce the leukemic phenotype. These arrays were analyzed in comparison to high-density gene promoter methylation arrays. Our data identified members of the WNT pathway as direct targets of E2a-Pbx1. Expression data from E2a-Pbx1 silenced cells support this finding as they demonstrate a functional regulation of this pathway. We further show a differential impact of E2a-Pbx1 silencing on the miRNA profile and identify E2a-Pbx1 dependent miRNAs. Using CGH arrays on primary E2a-Pbx1 samples we were able to pinpoint candidate secondary mutations as well as broad genetic categories: cases with 1q+, 1q+ combined with 9p-, and, separately, cases with +8. In summary we present direct and functional E2a-Pbx1 targets as well as candidate secondary mutations. We propose a model were direct and functional E2a- Pbx1 driven pathways that might include both genes and miRNAs might collaborate with identified auxiliary events to produce the E2a-Pbx1 leukemia.

Genome-Wide Mapping of Binding Sites and Networks of Potential Target Genes of the Fusion Oncogene ETV6/RUNX1 in Acute Lymphoblastic Leukemia in Childhood

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3776-3776
Author(s):  
Katja Kaulfuss ◽  
Thomas Heiden ◽  
Jochen Hecht ◽  
Karl Seeger
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chromatin Condensation ◽  
Chromosomal Translocation ◽  
Cellular Transformation ◽  
Gene Promoters ◽  
Childhood All

Abstract Acute lymphoblastic leukemia (ALL) in childhood, a clinically and biologically heterogeneous disease, represents the most common malignant disease in childhood. Approximately 20-25% of B-cell precursor ALL (BCP-ALL) carry the cryptic chromosomal translocation t(12;21)(p13;q22), the most common reciprocal chromosomal translocation in childhood ALL. This translocation combines two transcription factors and essential regulators of normal hematopoiesis, ETV6 and RUNX1, into the fusion oncogene ETV6/RUNX1 (E/R; synonym TEL/AML1). Recent studies in various animal models have strengthened the view that E/R positive cells give rise to preleukemic clones with a differentiation block in the pro/pre-B stage of B cell development that, after acquisition of additional mutations, may transform into full malignancy. Regarding the molecular mechanism by which the chimeric fusion protein E/R causes gene expression changes, it is assumed that E/R binds with the runt homology domain of RUNX1 (RHD, DNA-binding domain) to RUNX1 target sequences of gene promoters and recruits corepressors and histone deacetylases through its ETV6 portion, leading to chromatin condensation and transcriptional repression. Thus, E/R appears to act mainly as an epigenetic repressor of genes that are normally activated by RUNX1. However, the precise mechanism of cellular transformation and the identity of E/R target genes are largely unknown. Therefore, we used chromatin immunoprecipitation (ChIP), followed by next generation sequencing (ChIP-Seq) to identify E/R target genes in the E/R positive BCP-ALL cell lines REH and UoC-B6 as well as in primary patient material from children with relapsed E/R positive ALL. We were able to detect a core gene set of 335 candidate target genes common to all samples analyzed. Those genes could be assigned to 15 significantly overrepresented KEGG pathways (e.g. cell cycle, pathways in cancer, hematopoietic cell lineage and B cell receptor signaling pathway). The results show, besides target genes already reported in the literature such as EPOR, MPO and IGLL1, numerous not previously described candidate E/R target genes, such as LEF1, E2F2, FLT3, FGFR1 and RUNX1 that are potentially important in the pathogenesis of E/R positive ALL and may lead to new treatment options. Disclosures No relevant conflicts of interest to declare.

scholarly journals mSin3A/Histone Deacetylase 2- and PRMT5-Containing Brg1 Complex Is Involved in Transcriptional Repression of the Myc Target Gene cad

2003 ◽  
Vol 23 (21) ◽  
pp. 7475-7487 ◽  
Author(s):  
Sharmistha Pal ◽  
Romy Yun ◽  
Antara Datta ◽  
Lynne Lacomis ◽  
Hediye Erdjument-Bromage ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Carbamoyl Phosphate ◽  
Histone Deacetylase 2 ◽  
Protein Protein Interaction ◽  
Corepressor Complex ◽  
Expression Of Genes ◽  
In Cells

ABSTRACT The role of hSWI/SNF complexes in transcriptional activation is well characterized; however, little is known about their function in transcriptional repression. We have previously shown that subunits of the mSin3A/histone deacetylase 2 (HDAC2) corepressor complex copurify with hSWI/SNF complexes. Here we show that the type II arginine-specific methyltransferase PRMT5, which is involved in cyclin E repression, can be found in association with Brg1 and hBrm-based hSWI/SNF complexes. We also show that hSWI/SNF-associated PRMT5 can methylate hypoacetylated histones H3 and H4 more efficiently than hyperacetylated histones H3 and H4. Protein-protein interaction studies indicate that PRMT5 and mSin3A interact with the same hSWI/SNF subunits as those targeted by c-Myc. These observations prompted us to examine the expression profile of the c-Myc target genes, carbamoyl-phosphate synthase-aspartate carbamoyltransferase-dihydroorotase (cad) and nucleolin (nuc). We found that cad repression is altered in cells that express inactive Brg1 and in cells treated with the HDAC inhibitor depsipeptide. Using chromatin immunoprecipitation assays, we found that Brg1, mSin3A, HDAC2, and PRMT5 are directly recruited to the cad promoter. These results suggest that hSWI/SNF complexes, through their ability to interact with activator and repressor proteins, control expression of genes involved in cell growth and proliferation.

P1941The nuclear receptor corepressor 1 blocks CD36-mediated foam cell formation in atherogenesis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Oppi ◽  
S Stein ◽  
V Marzolla ◽  
E Osto ◽  
Z Rancic ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Foam Cell ◽  
Foam Cell Formation ◽  
High Cholesterol Diet ◽  
Peroxisome Proliferator ◽  
Aortic Sinus ◽  
Protective Function ◽  
Nuclear Receptor Corepressor

Abstract Background Nuclear receptors and their cofactors regulate the expression of various target genes in different tissue and organs to orchestrate downstream (patho)physiological processes. Although the function of several nuclear receptors in atherosclerosis has been studied, very little is known about the role of nuclear receptor cofactors in atherosclerosis. Given its important role to suppress inflammatory processes, we speculated that macrophage nuclear receptor corepressor 1 (NCOR1) plays a protective function in atherosclerosis development. Purpose To evaluate the contribution of macrophage NCOR1 in atherosclerosis we used myeloid cell-specific Ncor1 knockout mice on an atherosclerosis-prone background. Methods and results 8-week-old male and female mice were exposed to a high high-cholesterol diet for 12 weeks. Our findings demonstrate that the lack of macrophage Ncor1 leads to a severe atherosclerotic phenotype in both sexes. These mice show a higher content of plaques along the thoraco-abdominal aortae as well as at the aortic sinus, which were characterized by larger necrotic cores and thinner fibrous caps, a typical signature of unstable plaques. Moreover, we found that the pro-atherogenic effects of the Ncor1 deletion are mediated via derepression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, especially the enhanced expression of the CD36 scavenger receptor and the subsequent rise in oxLDL uptake. Interestingly, while the expression of NCOR1 is reduced, the PPARγ signature is increased in human atherosclerotic plaques, and this signature is further pronounced in ruptured compared to stable carotid plaques. Conclusion Our findings suggest that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and prevents the disease development. Acknowledgement/Funding The Swiss National Science Foundation, the Novartis Foundation, Olga-Mayenfisch Foundation, the OPO foundation

scholarly journals RBP-Jκ/SHARP Recruits CtIP/CtBP Corepressors To Silence Notch Target Genes

2005 ◽  
Vol 25 (23) ◽  
pp. 10379-10390 ◽  
Author(s):  
Franz Oswald ◽  
Michael Winkler ◽  
Ying Cao ◽  
Kathy Astrahantseff ◽  
Soizic Bourteele ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Target Gene ◽  
Animal Species ◽  
Target Genes ◽  
Dna Binding Protein ◽  
Dominant Negative ◽  
Cell Fates ◽  
Corepressor Complex ◽  
Necessary And Sufficient ◽  
Repression Domain

ABSTRACT Notch is a transmembrane receptor that determines cell fates and pattern formation in all animal species. After ligand binding, proteolytic cleavage steps occur and the intracellular part of Notch translocates to the nucleus, where it targets the DNA-binding protein RBP-Jκ/CBF1. In the absence of Notch, RBP-Jκ represses Notch target genes through the recruitment of a corepressor complex. We and others have identified SHARP as a component of this complex. Here, we functionally demonstrate that the SHARP repression domain is necessary and sufficient to repress transcription and that the absence of this domain causes a dominant negative Notch-like phenotype. We identify the CtIP and CtBP corepressors as novel components of the human RBP-Jκ/SHARP-corepressor complex and show that CtIP binds directly to the SHARP repression domain. Functionally, CtIP and CtBP augment SHARP-mediated repression. Transcriptional repression of the Notch target gene Hey1 is abolished in CtBP-deficient cells or after the functional knockout of CtBP. Furthermore, the endogenous Hey1 promoter is derepressed in CtBP-deficient cells. We propose that a corepressor complex containing CtIP/CtBP facilitates RBP-Jκ/SHARP-mediated repression of Notch target genes.

Epigenetic Regulation of Cell Cycle-Promoting Genes By Ikaros and HDAC1 in Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3571-3571
Author(s):  
Sunil Muthusami ◽  
Chunhua Song ◽  
Xiaokang Pan ◽  
Chandrika S. Gowda ◽  
Kimberly J Payne ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromatin Remodeling ◽  
Transcriptional Repression ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Promoter Regions ◽  
Cycle Progression ◽  
Repressive Chromatin

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood leukemia. Expression profiling has identified IKZF1 (Ikaros) as a major tumor suppressor in B-ALL and established reduced Ikaros function as a poor prognostic marker for this disease. Ikaros regulates expression of its target genes via chromatin remodeling. In vivo, Ikaros can form a complex with histone deacetylases HDAC1 and/or HDAC2 as well as the NuRD chromatin remodeling complex. The mechanisms by which Ikaros exerts its tumor suppressor function and regulates gene expression in B-ALL are unknown. Here we report the use of chromatin immunoprecipitation coupled with next generation sequencing (ChIP-SEQ) to identify genes that are regulated by Ikaros in vivo and to determine the role of Ikaros in chromatin remodeling in B-ALL. Results reveal that Ikaros binds to the promoter regions of a large number of genes that are critical for cell cycle progression. These include CDC2, CDC16, CDC25A, ANAPC1, and ANAPC7. Overexpression of Ikaros in leukemia cells resulted in transcriptional repression of Ikaros target genes. Results from luciferase reporter assays performed using the respective promoters of Ikaros target genes support a role for Ikaros as a transcriptional repressor of these genes. Downregulation of Ikaros by siRNA resulted in increased expression of Ikaros target genes that control cell cycle progression. These results suggest that Ikaros functions as a negative regulator of cell cycle progression by repressing transcription of cell cycle-promoting genes. Next, we studied how Ikaros binding affects the epigenetic signature at promoters of Ikaros target genes. Global epigenetic mapping showed that Ikaros binding at the promoter region of cell cycle-promoting genes is associated with the formation of one of two types of repressive epigenetic marks – either H3K27me3 or H3K9me3. While these epigenetic marks were mutually exclusive, they were both associated with the loss of H3K9 acetylation and transcriptional repression. Serial qChIP assays spanning promoters of the Ikaros target genes revealed that the presence of H3K27me3 is associated with Ikaros and HDAC1 binding, while the H3K9me3 modification is associated with Ikaros binding and the absence of HDAC1. ChIP-SEQ analysis of HDAC1 global genomic binding demonstrated that over 80% of H3K27me3 modifications at promoter regions are associated with HDAC1 binding at surrounding sites. The treatment of leukemia cells with the histone deacetylase inhibitor – trichostatin (TSA) resulted in a severe reduction of global levels of H3K27me3, as evidenced by Wesern blot. These data suggest that HDAC1 activity in leukemia is essential for the formation of repressive chromatin that is characterized by the presence of H3K27me3. Our data suggest that Ikaros binding at the promoters of its target genes can result in the formation of repressive chromatin by two distinct mechanisms: 1) direct Ikaros binding resulting in increased H3K9me3 or 2) Ikaros recruitment of HDAC1 with increased H3K27me3 modifications. These data suggest distinct mechanisms for the regulation of chromatin remodeling and target gene expression by Ikaros alone, and Ikaros in complex with HDAC1. In conclusion, the presented data suggest that HDAC1 has a key role in regulating cell cycle progression and proliferation in B-ALL. Our results identify novel, Ikaros-mediated mechanisms of epigenetic regulation that contribute to tumor suppression in leukemia. Supported by National Institutes of Health R01 HL095120, and the Four Diamonds Fund Endowment. Disclosures No relevant conflicts of interest to declare.

The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 946-954 ◽  
Author(s):  
Jelena Popović ◽  
Liang-Ping Li ◽  
Peter Michael Kloetzel ◽  
Matthias Leisegang ◽  
Wolfgang Uckert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Cell Epitope ◽  
Chimeric Protein ◽  
Chromosomal Translocation ◽  
Cell Receptor ◽  
T Cell Response ◽  
Adoptive Therapy

Abstract Adoptive therapy with T-cell receptor (TCR)–engineered T cells is a promising approach in cancer treatment. While usage of T cells specific for tumor-associated antigens (TAAs) can lead to serious side effects because of autoimmunity, targeting true tumor-specific mutations, such as the products of translocations in leukemias, should reduce such a risk. A potentially ideal target might be the chimeric protein TEL-AML1, which results from the chromosomal translocation 12;21 and represents the most common fusion gene in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Within the fusion region of TEL-AML1, a single epitope has been described by reverse immunology as immunogenic in HLA-A*0201 restriction settings. As a potential source of TCRs specific for this TEL-AML1 epitope, we have used mice expressing a human TCR-αβ repertoire and human MHC class I. Surprisingly, we have found that, although a specific functional CD8+ T-cell response against this peptide could be evoked, the described epitope was in fact not endogenously processed. Analyses done with a potent antigen-presenting cell line, as well as with purified human proteasomes, support the conclusion that this peptide cannot be proposed as a potential target in immunotherapy of ALL in HLA-A*0201-restricted fashion.

Sign in / Sign up

Export Citation Format

Share Document