Academic literature on the topic 'Core Binding Factor Alpha 3 Subunit'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the lists of relevant articles, books, theses, conference reports, and other scholarly sources on the topic 'Core Binding Factor Alpha 3 Subunit.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Journal articles on the topic "Core Binding Factor Alpha 3 Subunit"
1
Nuchprayoon, I., S. Meyers, L. M. Scott, J. Suzow, S. Hiebert, and A. D. Friedman. "PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2 beta/CBF beta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells." Molecular and Cellular Biology 14, no. 8 (August 1994): 5558–68. http://dx.doi.org/10.1128/mcb.14.8.5558.
Full textAbstract:
The myeloperoxidase (MPO) and neutrophil elastase genes are expressed specifically in immature myeloid cells. The integrity of a polyomavirus enhancer core sequence, 5'-AACCACA-3', is critical to the activity of the murine MPO proximal enhancer. This element binds two species, myeloid nuclear factors 1 alpha and 1 beta (MyNF1 alpha and -beta), present in 32D cl3 myeloid cell nuclear extracts. The levels of the MyNF1s increase during early 32D cl3 cell granulocytic differentiation. Both MyNF1 alpha and -beta supershift with an antiserum raised by using a peptide derived from the N terminus of polyomavirus enhancer-binding protein 2/core-binding factor (PEBP2/CBF) alpha subunit. The specific peptide inhibits these supershifts. In vitro-translated PEBP2/CBF DNA-binding domain binds the murine MPO PEBP2/CBF site. An alternate PEBP2/CBF consensus site, 5'-GACCGCA-3', but not a simian virus 40 enhancer core sequence, 5'-TTCCACA-3', binds the MyNF1s in vitro and activates a minimal murine MPO-thymidine kinase promoter in vivo. The murine neutrophil elastase gene 100-bp 5'-flanking sequences contain several functional elements, including potential binding sites for PU.1, C/EBP, c-Myb, and PEBP2/CBF. The functional element 5'-GGCCACA-3' located at positions -66 to 72 differs from the PEBP2/CBF consensus (5'-PuACCPuCA-3') only by an A-to-G transition at position 2. This DNA element binds MyNF1 alpha and -beta weakly. The N terminis of two PEBP2/CBF alpha subunit family members, PEBP2 alpha A and PEBP2 alpha B (murine AML1), are nearly identical, and 32D c13 cl3 cells contain both corresponding mRNAs. Since t(8;21), t(3;21), and inv(16), associated with myeloid leukemias, disrupt subunits of PEBP2/CBF, we speculate that the resulting oncoproteins, AML1-ETO, AML1-EAP, AML1-Evi1, and CBF beta-MYH11, inhibit early myeloid differentiation.
2
Nuchprayoon, I., S. Meyers, L. M. Scott, J. Suzow, S. Hiebert, and A. D. Friedman. "PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2 beta/CBF beta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells." Molecular and Cellular Biology 14, no. 8 (August 1994): 5558–68. http://dx.doi.org/10.1128/mcb.14.8.5558-5568.1994.
Full textAbstract:
The myeloperoxidase (MPO) and neutrophil elastase genes are expressed specifically in immature myeloid cells. The integrity of a polyomavirus enhancer core sequence, 5'-AACCACA-3', is critical to the activity of the murine MPO proximal enhancer. This element binds two species, myeloid nuclear factors 1 alpha and 1 beta (MyNF1 alpha and -beta), present in 32D cl3 myeloid cell nuclear extracts. The levels of the MyNF1s increase during early 32D cl3 cell granulocytic differentiation. Both MyNF1 alpha and -beta supershift with an antiserum raised by using a peptide derived from the N terminus of polyomavirus enhancer-binding protein 2/core-binding factor (PEBP2/CBF) alpha subunit. The specific peptide inhibits these supershifts. In vitro-translated PEBP2/CBF DNA-binding domain binds the murine MPO PEBP2/CBF site. An alternate PEBP2/CBF consensus site, 5'-GACCGCA-3', but not a simian virus 40 enhancer core sequence, 5'-TTCCACA-3', binds the MyNF1s in vitro and activates a minimal murine MPO-thymidine kinase promoter in vivo. The murine neutrophil elastase gene 100-bp 5'-flanking sequences contain several functional elements, including potential binding sites for PU.1, C/EBP, c-Myb, and PEBP2/CBF. The functional element 5'-GGCCACA-3' located at positions -66 to 72 differs from the PEBP2/CBF consensus (5'-PuACCPuCA-3') only by an A-to-G transition at position 2. This DNA element binds MyNF1 alpha and -beta weakly. The N terminis of two PEBP2/CBF alpha subunit family members, PEBP2 alpha A and PEBP2 alpha B (murine AML1), are nearly identical, and 32D c13 cl3 cells contain both corresponding mRNAs. Since t(8;21), t(3;21), and inv(16), associated with myeloid leukemias, disrupt subunits of PEBP2/CBF, we speculate that the resulting oncoproteins, AML1-ETO, AML1-EAP, AML1-Evi1, and CBF beta-MYH11, inhibit early myeloid differentiation.
3
Steensma, David P., Richard J. Gibbons, Ruben A. Mesa, Ayalew Tefferi, and Douglas R. Higgs. "Somatic Point Mutations in RUNX1/CBFA2/AML1 Are Common in High-Risk Myelodysplastic Syndrome, but Not in Myelofibrosis with Myeloid Metaplasia." Blood 104, no. 11 (November 16, 2004): 2438. http://dx.doi.org/10.1182/blood.v104.11.2438.2438.
Full textAbstract:
Abstract Introduction: The core-binding factor subunit RUNX1/CBFA2/AML1 (Runt-related transcription factor 1, Core-binding factor alpha 2 subunit, Oncogene AML1) is critical for generation of hematopoietic stem cells during embryogenesis and for normal megakaryopoiesis in adults. RUNX1/CBFA2/AML1 has long been recognized as an oncogene, and is frequently involved in leukemia-associated translocations that create aberrant fusion proteins (e.g., AML1-ETO). Recently, acquired somatic point mutations in the RUNX1/CBFA2/AML1 gene have been described in a subset of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). These point mutations are associated with the loss of normal RUNX1 trans-activation potential and/or altered binding to the non-DNA-binding subunit of core-binding factor, CBFB. Given the importance of core-binding factor in megakaryocytic differentiation and platelet production and the central role of megakaryocytes in the pathophysiology of myelofibrosis with myeloid metaplasia (MMM), and in light of the myelofibrotic phenotype of GATA-1low mice (GATA-1 and RUNX1 are co-expressed and co-operate in megakaryocytic differentiation), we hypothesized that RUNX1 gene mutations might be common in MMM. In addition, we wanted to know whether patients with MDS-associated acquired alpha thalassemia (i.e., ATMDS), a special MDS subgroup with a very high incidence of point mutations in the X-linked ATRX gene, have an especially high incidence of RUNX1 mutations that might account for the more severe hematopoietic defect found in these patients compared with boys with inherited ATR-X syndrome (detailed in Steensma et al, Blood2004;103:2019). Methods and Results: We analyzed samples from 26 well-characterized patients with MMM and from 52 with MDS (11 RA, 3 RARS, 8 RCMD, 3 RAEB-1, 7 RAEB-2, 2 MDS in transition to AML-M6, 14 atypical/unclassifable MDS, 4 MDS subtype unknown - including 18 with ATMDS) for RUNX1 point mutations by denaturing high-performance liquid chromatography (DHPLC) followed by subcloning and sequencing of samples exhibiting heteroduplex peaks. We found 5 RUNX1 mutations in MDS patients (9.6%), all of whom had RAEB-2 (4 patients) or a history of treated AML (1 patient), but detected no mutations in MMM patients. All patients with RUNX1 mutations progressed to overt leukemia within 1 year. ATMDS patients did not have an increased risk of RUNX1 point mutations (2/18 patients with mutations, 11.1%) when compared with MDS without thalassemia (3/34 patients, 8.8%; p=0.58). Additionally, 1 MDS patient had a clonally restricted mutation in GATA-1 (c.1066 C>T) (also screened by DHPLC), but this is not predicted to change the GATA-1 amino acid sequence and is likely a random event reflecting the genomic instability characteristic of MDS. Conclusion: RUNX1 point mutations are common in high-risk MDS, but not in MMM, and that ATMDS patients do not have a risk of RUNX1 mutations in excess of that expected for MDS in general.
4
Hamey, Fiona K., Sonia Nestorowa, Sarah J. Kinston, David G. Kent, Nicola K. Wilson, and Berthold Göttgens. "Reconstructing blood stem cell regulatory network models from single-cell molecular profiles." Proceedings of the National Academy of Sciences 114, no. 23 (June 5, 2017): 5822–29. http://dx.doi.org/10.1073/pnas.1610609114.
Full textAbstract:
Adult blood contains a mixture of mature cell types, each with specialized functions. Single hematopoietic stem cells (HSCs) have been functionally shown to generate all mature cell types for the lifetime of the organism. Differentiation of HSCs toward alternative lineages must be balanced at the population level by the fate decisions made by individual cells. Transcription factors play a key role in regulating these decisions and operate within organized regulatory programs that can be modeled as transcriptional regulatory networks. As dysregulation of single HSC fate decisions is linked to fatal malignancies such as leukemia, it is important to understand how these decisions are controlled on a cell-by-cell basis. Here we developed and applied a network inference method, exploiting the ability to infer dynamic information from single-cell snapshot expression data based on expression profiles of 48 genes in 2,167 blood stem and progenitor cells. This approach allowed us to infer transcriptional regulatory network models that recapitulated differentiation of HSCs into progenitor cell types, focusing on trajectories toward megakaryocyte–erythrocyte progenitors and lymphoid-primed multipotent progenitors. By comparing these two models, we identified and subsequently experimentally validated a difference in the regulation of nuclear factor, erythroid 2 (Nfe2) and core-binding factor, runt domain, alpha subunit 2, translocated to, 3 homolog (Cbfa2t3h) by the transcription factor Gata2. Our approach confirms known aspects of hematopoiesis, provides hypotheses about regulation of HSC differentiation, and is widely applicable to other hierarchical biological systems to uncover regulatory relationships.
5
Qi, Xiangjun, Hongbin Xu, Peng Zhang, Guoming Chen, Zhiqiang Chen, Caishan Fang, and Lizhu Lin. "Investigating the Mechanism of Scutellariae barbata Herba in the Treatment of Colorectal Cancer by Network Pharmacology and Molecular Docking." Evidence-Based Complementary and Alternative Medicine 2021 (August 2, 2021): 1–18. http://dx.doi.org/10.1155/2021/3905367.
Full textAbstract:
Background. Colorectal cancer (CRC) is one of the most common gastrointestinal tumors, which accounts for approximately 10% of all diagnosed cancers and cancer deaths worldwide per year. Scutellariae barbatae Herba (SBH) is one of the most frequently used traditional Chinese medicine (TCM) in the treatment of CRC. Although many experiments have been carried out to explain the mechanisms of SBH, the mechanisms of SBH have not been illuminated fully. Thus, we constructed a network pharmacology and molecular docking to investigate the mechanisms of SBH. Methods. We adopted active constituent prescreening, target predicting, protein-protein interaction (PPI) analysis, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, differentially expressed gene analysis, and molecular docking to establish a system pharmacology database of SBH against CRC. Results. A total of 64 active constituents of SBH were obtained and 377 targets were predicted, and the result indicated that quercetin, luteolin, wogonin, and apigenin were the main active constituents of SBH. Glucocorticoid receptor (NR3C1), pPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA), cellular tumor antigen p53 (TP53), transcription factor AP-1 (JUN), mitogen-activated protein kinase 1 (MAPK1), Myc protooncogene protein (MYC), cyclin-dependent kinase 1 (CDK1), and broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2) were the major targets of SBH in the treatment of CRC. GO analysis illustrated that the core biological process regulated by SBH was the regulation of the cell cycle. Thirty pathways were presented and 8 pathways related to CRC were involved. Molecular docking presented the binding details of 3 key targets with 6 active constituents. Conclusions. The mechanisms of SBH against CRC depend on the synergistic effect of multiple active constituents, multiple targets, and multiple pathways.
6
Cammenga, Jorg, Gabriela Putz, Birte Niebuhr, Stefan Horn, Ulla Bergholz, Frank Buchholz, and Carol Stocking. "The Role of RUNX1 DNA-Binding Mutations in Acute Myeloid Leukemia." Blood 106, no. 11 (November 16, 2005): 1373. http://dx.doi.org/10.1182/blood.v106.11.1373.1373.
Full textAbstract:
Abstract The RUNX1 gene encodes an alpha subunit of the core-binding factor (CBF), an important heterodimeric transcription factor in hematopoietic ontogeny and development, and is one of the most frequently disrupted genes in acute leukemia. In addition to its involvement in several translocations, the RUNX1 gene is often subject to deletions or point mutations in acute myelogenous leukemia (AML). Interestingly, in addition to complete loss-of-function mutations, many of the alterations involve missense point mutations within the Runt domain that disrupt DNA binding activity (DB-mutants). In vitro assays have suggested that these DB mutants have a dominant-negative (DN) activity, presumably due to their ability to bind and sequester CBF beta but inability to bind DNA. A strict correlation between the type of mutation and its monoallelic or biallelic incidence is not apparent even though a DN mutant should only affect one allele while a loss of function mutation should affect both alleles. It has been hypothesized that loss of one allele (haploinsufficiency) is sufficient for loss of tumor suppressor activity but the relative high incidence of specific DB mutations suggests a more complex scenario. We thus sought to determine if expression of DB mutants in murine bone marrow (BM) resulted in a similar phenotype as the loss of Runx1, or if these mutations are associated with a gain-of-function. Two RUNX1-DB mutants were thus evaluated using the established retroviral transduction/transplantation mouse model. Between 3 and 6 months after transplantation, peripheral blood, spleen and BM cells were analyzed. Long-term repopulating cells expressing RUNX1 DB-mutants were able to contribute normally to both myeloid and lymphoid compartments, although a disproportionate increase in the B-cell compartment was observed in 3 out of 10 mice. Surprisingly, and inconsistent with a DN activity, disruption of normal T-cell or megakaryocytic development was not observed in the mice, in contrast to Runx1−/+ mice. Significantly, however, replating assays in vitro demonstrated that RUNX1-DB mutants lead to a significant increase in self-renewal activity, in contrast to BM cells of floxed Runx1 mice expressing the Cre recombinase, which showed a less dramatic effect on self-renewal. Colonies derived from CFU-Cs expressing RUNX1-DB mutants were composed of dysplastic granulocytic and monocytic cells, with an increasing number of immature blasts after multiple replatings (>7), whereas residual colonies from Runx1fl/− BM receiving CRE showed a different morphology with more mature cells. Thus our data suggest that RUNX1-DB mutants do not act in a dominant negative fashion to inhibit normal RUNX1 function, but impart a gain-of-function that results in impaired myeloid differentiation and increased self-renewal potential, consistent with its association with AML.
7
Fang, Yue, Xinquan Liu, and Jing Su. "Network Pharmacology Analysis of Traditional Chinese Medicine Formula Shuang Di Shou Zhen Tablets Treating Nonexudative Age-Related Macular Degeneration." Evidence-Based Complementary and Alternative Medicine 2021 (March 24, 2021): 1–14. http://dx.doi.org/10.1155/2021/6657521.
Full textAbstract:
Objective. To analyze the pharmacological mechanism of the treatment of dry age-related macular degeneration (dry AMD) based on a network pharmacological approach of Shuang Di Shou Zhen Tablets (SDSZT) and to provide a new reference for the current lack of effective treatment of dry AMD. Methods. The main chemical constituents and their targets of Rehmanniae Radix Praeparata, Ligustrum lucidum, Mori Fructus, Paeonia albiflora, Rhizoma Dioscoreae, Alisma orientale, Schisandra chinensis, Radix Polygoni Multiflori Preparata, Ophiopogon japonicus, and Radix Rehmanniae were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID). The active ingredients of traditional Chinese medicine were screened according to Absorption, Distribution, Metabolism, and Excretion (ADME), the gene names of the targets of each active ingredient were obtained from the Uniprot database, the main targets of dry AMD were obtained from GeneCards and DisGeNET database, and the protein interaction analysis was performed on the String database. The Metascape database was used to analyze the “drug-component-target” and the biological processes and networks involved, and then, Cytoscape 3.8.1 was used to construct the “ SDSZT component-dry AMD target-pathway” network. Results. The main active ingredients of SDSZT for dry AMD treatment are quercetin, kaempferol, luteolin, β-glutamine, β-carotene, etc. And, the core targets are RAC-alpha serine/threonine-protein kinase (AKT1), prostaglandin G/H synthase 1 (PTGS1), tumor necrosis factor (TNF), transcription factor AP-1 (JUN), apoptosis regulator Bcl-2 (BCL2), caspase-3 (CASP3), phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG), androgen receptor (AR), apoptosis regulator BAX (BAX), etc. The biological pathways for the treatment of age-related macular degeneration by SDSZT mainly act on pathways in cancer, fluid shear stress and atherosclerosis, and TNF signaling pathway, and the main function of SDSZT is to regulate intracellular cytokine receptor binding. Conclusion. This study initially reveals the multiconstituent, multitarget, and multipathway mechanism of action of SDSZT in the treatment of dry AMD and provides the basis for the clinical application of SDSZT.
8
Burda, Pavel, Nikola Curik, Juraj Kokavec, Dana Mikulenkova, Arthur Skoultchi, Jiri Zavadil, and Tomas Stopka. "PU.1 Relieves Its GATA-1-Mediated Repression near Cebpa and Cbfb During Transdifferentiation of Murine Erythroleukemia - Tool of Inducing Leukemic Blasts to Differentiate." Blood 114, no. 22 (November 20, 2009): 547. http://dx.doi.org/10.1182/blood.v114.22.547.547.
Full textAbstract:
Abstract Abstract 547 Transcription factors GATA-1 and PU.1 interact on DNA to block transcriptional programs of undesired lineage during hematopoietic commitment. Murine erythroleukemia (MEL) cells that co-express GATA-1 and PU.1 are blocked at the blast stage but respond to down-regulation of PU.1 or up-regulation of GATA-1 by inducing terminal erythroid differentiation. To test whether GATA-1 blocks PU.1 in MEL cells we have conditionally activated a transgenic PU.1 protein fused with the estrogen receptor ligand-binding domain (PUER), resulting in activation of a myeloid transcriptional program. Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein (C/EBP) alpha (Cebpa) and Core-binding factor, beta subunit (Cbfb) that encode two key hematopoietic transcription factors. Inhibition of GATA-1 by siRNA resulted in derepression of PU.1 target genes. Chromatin immunoprecipitation and reporter assays identified PU.1 motif sequences near Cebpa and Cbfb co-occupied by PU.1 and GATA-1 in the leukemic blasts. Substantial derepression of Cebpa and Cbfb is achieved in MEL cells by either activation of PU.1 or knockdown of GATA-1. Furthermore, transcriptional regulation of these loci by manipulating the levels of PU.1 and GATA-1 involves quantitative increases in a transcriptionally active chromatin mark: acetylation of histone H3K9. Collectively, we demonstrate that either activation of PU.1 or inhibition of GATA-1 efficiently reverse the transcriptional block imposed by GATA-1 and lead to activation of a myeloid transcriptional program directed by PU.1. The mechanism of PU.1 and GATA-1 in leukemic state and upon leukemia differentiation involves the following putative steps: at myeloid genes such as Cebpa, PU.1 binds directly to DNA but is repressed by GATA1 that binds directly to PU.1 molecules on DNA. Activation of PU.1-ER and stable levels of GATA-1 create excess of availabel PU.1, which is not paired by availabel GATA-1 on DNA, allowing thus gene activation. Similarly, on erythroid genes such as Nfe2, GATA1 is bound to DNA, but is repressed by PU.1 that binds to this GATA-1 molecule. Activation of GATA1-ER creates an excess of availabel GATA-1 which is not paired on DNA by availabel PU.1, also allowing gene activation. Our mechanistic study implicates that transcription factor manipulation, such as inhibition of GATA-1 or activation of PU.1 in erythroleukemias, may represent an efficient tool of inducing leukemic blasts to differentiate. (Grants NR9021-4, 10310-3, 2B06077) Disclosures: No relevant conflicts of interest to declare.
9
Stopka, Tomas, Pavel Burda, Petra Basova, Karin Vargova, Nikola Curik, Anna Jonasova, and Marek Trneny. "5-Azacytidine and G-CSF Derepressed Chromatin Structure of PU.1 and Its Targets Cebpa and Cbfb In Myelodysplastic Syndrome (MDS)." Blood 116, no. 21 (November 19, 2010): 124. http://dx.doi.org/10.1182/blood.v116.21.124.124.
Full textAbstract:
Abstract Abstract 124 The myelodysplastic syndrome (MDS) represents a heterogeneous disorder characterized by ineffective hematopoiesis and evolution to acute myelogenous leukemia that is strikingly refractory to current therapeutic approaches. Novel epigenetic drugs including DNA-methyltransferase inhibitor 5-Azacitidine (5-AZA, Vidaza) are currently considered to improve clinical response in patients with MDS. MDS is characterized by abnormal differentiation and blocked maturation responsive to 5-AZA, therefore we studied major regulator of hematopoietic differentiation, transcription factor PU.1 as a candidate target of the epigenetic therapy. Transcription factor PU.1 represents very important myelo-lymphoid regulator of differentiation. PU.1 expression is regulated by Upstream Regulatory Element (URE) and its deletion in mouse caused downregulation of PU.1 leading to acute leukemia (Rosenbauer 2004). Our laboratory recently demonstrated that PU.1 in murine acute leukemic cells binds and promotes derepression of CCAAT/enhancer binding protein (C/EBP) alpha (Cebpa) and Core-binding factor, beta subunit (Cbfb) (Burda 2009) that encode two key hematopoietic transcription factors involved in myeloid differentiation. Furthermore, transcriptional regulation through PU.1 binding sites of Cebpa and Cbfb loci involves quantitative increases in a transcriptionally active chromatin mark: acetylation of histone H3 lysine K9. Others reported that Cebpa expression is augmented by G-CSF (Dahl 2003). To determine if 5-AZA regulates PU.1 and its targets we determined their expression and chromatin structure following the 5-AZA treatment in MDS patient-derived blasts and in cell lines derived from MDS (MOLM-13, OCI-M2, SKM-1) and AML (K562). Our data provide evidence that in the chosen cell lines and in so far limited number of patients-derived cells (N=4) the gene expression of PU.1 and its direct targets Cebpa and Cbfb is stimulated by 5-AZA and this effect is further enhanced by G-CSF. Furthermore, marks of activated chromatin structure including histone H3K9 hyperacetylation and H3K4 hypermethylation are increased at the URE of the PU.1 gene again documenting its transcriptional activation. Conversely, levels of H3K9 methylation at URE are significantly reduced upon 5-AZA treatment documenting 5-AZA stimulates loss of repressive chromatin structure near PU.1 gene. These observations are currently compared with responsiveness of the patients to 5-AZA in vivo and expanded to larger set of patients. Our data collectively supports importance of the chromatin structure upstream of PU.1 gene and of its direct targets Cebpa and Cbfb in patients with MDS that may add to better understanding of effectiveness of epigenetic therapy in MDS. (Grants # IGA 10310-3, MSMT 2B06077, SVV-2010-254260507, MPO FR-TI2/509, GAUK 251135 82210). Disclosures: No relevant conflicts of interest to declare.
10
Kutny, Matthew A., Todd A. Alonzo, Robert B. Gerbing, Kristen Miller, Phoenix Ho, Nyla A. Heerema, Beverly Lange, Alan S. Gamis, and Soheil Meshinchi. "RUNX1 Mutations in Pediatric AML: A Report From the Children's Oncology Group." Blood 114, no. 22 (November 20, 2009): 2614. http://dx.doi.org/10.1182/blood.v114.22.2614.2614.
Full textAbstract:
Abstract Abstract 2614 Poster Board II-590 The RUNX1 gene (previously AML1) encodes the alpha subunit of core binding factor (CBFα), which is implicated in normal and malignant hematopoiesis. Translocations involving RUNX1 have been associated with favorable prognosis in acute leukemias (e.g., t(8;21) in AML and t(12;21) in ALL). Point mutations of RUNX1 have been identified in exon 3 and exon 8 of the RUNX1 gene in a subset of AML patients and are most closely associated with MDS associated AML and AML subtype M0. We evaluated the prevalence and prognostic significance of RUNX1 mutations in pediatric patients with de novo AML treated on pediatric AML trials CCG-2941 and CCG-2961. Initial evaluation of exon 3 and exon 8 of the RUNX1 gene was conducted on a cohort of 100 randomly selected patient specimens. In this initial analysis, we identified 4 missense mutations of exon 3 that caused a change in codon 56. No exon 8 mutations were identified. Subsequent molecular genotyping of the remaining 484 patient specimens were limited to exon 3. Of the 584 diagnostic specimens tested, a missense mutation of exon 3 was detected in 19 patients (3.3%). All detected mutations occurred at nucleotide 167 (T to C) causing a leucine to serine substitution at codon 56 (L56S). Additionally, two patients had a synonymous mutation (G to A at nucleotide 183, P61P) and were considered wild type. Demographics, laboratory characteristics and clinical outcome were compared between those with and without RUNX1 mutations. There was no significant difference with regard to age, gender or race between these groups. Those with RUNX1 mutations had a significantly lower prevalence of organomegaly (16% vs. 42%, p=0.02) and significantly higher rate of extramedullary disease (chloroma 26% vs. 10%, p=0.04). There was no significant difference in association with other known cytogenetic abnormalities or risk groupings (standard, low, or high risk grouping on these studies). t(8;21) translocations were detected in 22% of those with RUNX1 mutations compared to 16% in those without mutation (p=0.6), and there was no RUNX1 mutation detected in patients with inv(16). Of the 85 patients with FLT3/ITD, NPM1 or CEBPA mutations, only 3 patients had a concomitant RUNX1 mutation (2 with FLT3/ITD and 1 with NPM1 mutation). Remission induction rate was compared between patients with and without RUNX1 mutations. Those with RUNX1 mutations had a similar CR rate to those without mutations (89% vs. 79%, p=0.4). Overall survival from remission for patients with and without RUNX1 mutation was 39 ± 25% and 60 ± 5% respectively (p=0.1) with a corresponding disease-free survival of 34 ± 24% vs. 49 ± 5% (p=0.25). RUNX1 mutations may represent a biologically distinct group that presents in 3.3% of pediatric AML patients across different morphologic and cytogenetic populations. Alterations of RUNX1 affect signal transduction pathways and may be exploited in defining a population for directed and risk based therapy. Disclosures: No relevant conflicts of interest to declare.
Dissertations / Theses on the topic "Core Binding Factor Alpha 3 Subunit"
1
Pande, Sandhya. "Regulation of Runx Proteins in Human Cancers: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/559.
Full textAbstract:
Runt related transcription factors (Runx) play an important role in mammalian development by regulating the expression of key genes involved in cell proliferation, differentiation and growth. The work described in this thesis details the mechanisms by which the activity of two members of this family are regulated in human cells. Chapter One provides a brief introduction of Runx transcription factors.
Chapter Two describes the regulation of Runx2 protein by the PI3 kinase/Akt pathway in human breast cancer cells. The PI3 kinase/Akt pathway is one of the major signal transduction pathways through which growth factors influence cell proliferation and survival. It is also one of the most frequently dysregulated pathways in human cancers. We identify Runx2 protein, a key regulator of breast cancer invasion as a novel substrate of Akt kinase and map residues of Runx2 that are phosphorylated by Akt in breast cancer cells. Our results show that phosphorylation by Akt increases the binding of Runx2 protein to its target gene promoters and we identify the phosphorylation events that enhance DNA binding of Runx2. Our work establishes Runx2 protein as a critical effecter downstream of Akt that regulates breast cancer invasion.
In Chapter Three we describe the subnuclear localization of the tumor suppressor protein Runx3 during interphase and mitosis. We find that similar to other Runx family members, Runx3 protein resides in nuclear matrix associated foci during interphase. We delineate a subnuclear targeting signal that directs Runx3 to these nuclear matrix associated foci. Our work establishes that this association of Runx3 protein with the nuclear matrix plays a vital role in regulating its transcriptional activity.
Chromatin immunoprecipitation results show that Runx3 occupies rRNA promoters during interphase. We also find that Runx3 remains associated with chromosomes during mitosis and localizes with nucleolar organizing regions (NORs), reflecting an interaction with epigenetic potential.
This thesis provides novel insights into various mechanisms by which cells regulate the activity of Runx proteins.
2
Madera, Dmitri. "Cooperating Events in Core Binding Factor Leukemia Development: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/532.
Full textAbstract:
Leukemia is a hematopoietic cancer that is characterized by the abnormal differentiation and proliferation of hematopoietic cells. It is ranked 7th by death rate among cancer types in USA, even though it is not one of the top 10 cancers by incidence (USCS, 2010). This indicates an urgent need for more effective treatment strategies. In order to design the new ways of prevention and treatment of leukemia, it is important to understand the molecular mechanisms involved in development of the disease.
In this study, we investigated mechanisms involved in the development of acute myeloid leukemia (AML) that is associated with CBF fusion genes. The RUNX1 and CBFB genes that encode subunits of a transcriptional regulator complex CBF, are mutated in a subset (20 – 25%) of AML cases. As a result of these mutations, fusion genes called CBFB-MYH11 and RUNX1-ETO arise. The chimeric proteins encoded by the fusion genes provide block in proliferation for myeloid progenitors, but are not sufficient for AML development. Genetic studies have indicated that activation of cytokine receptor signaling is a major oncogenic pathway that cooperates in leukemia development. The main goal of my work was to determine a role of two factors that regulate cytokine signaling activity, the microRNA cluster miR-17-92 and the thrombopoietin receptor MPL, in their potential cooperation with the CBF fusions in AML development.
We determined that the miR-17-92 miRNA cluster cooperates with Cbfb-MYH11 in AML development in a mouse model of human CBFB-MYH11 AML. We found that the miR-17-92 cluster downregulates Pten and activates the PI3K/Akt pathway in the leukemic blasts. We also demonstrated that miR-17-92 provides an anti-apoptotic effect in the leukemic cells, but does not seem to affect proliferation. The anti-apoptotic effect was mainly due to activity of miR-17 and miR-20a, but not miR-19a and miR-19b.
Our second study demonstrated that wild type Mpl cooperated with RUNX1-ETO fusion in development of AML in mice. Mpl induced PI3K/Akt, Ras/Raf/Erk and Jak2/Stat5 signaling pathways in the AML cells. We showed that PIK3/Akt pathway plays a role in AML development both in vitro and in vivo by increasing survival of leukemic cells. The levels of MPL transcript in the AML samples correlated with their response to thrombopoietin (THPO). Moreover, we demonstrated that MPL provides pro-proliferative effect for the leukemic cells, and that the effect can be abrogated with inhibitors of PI3K/AKT and MEK/ERK pathways.
Taken together, these data confirm important roles for the PI3K/AKT and RAS/RAF/MEK pathways in the pathogenesis of AML, identifies two novel genes that can serve as secondary mutations in CBF fusions-associated AML, and in general expands our knowledge of mechanisms of leukemogenesis.
3
Montelius, Andreas. "Role of transcription factors in sensory neuron specification /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-115-9/.
Full text
4
Theriault, Francesca M. "Regulation of neuronal diversity in the mammalian nervous system." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103300.
Full textAbstract:
To acquire its characteristic structural and functional complexity, the mammalian nervous system must undergo several critical developmental processes. One such process requires factors that regulate the decision of dividing progenitors to leave the cell cycle and activate the neuronal differentiation program. It is shown in this thesis that the murine runt-related gene Runx1 is expressed in proliferating cells on the basal side of the murine olfactory epithelium. Disruption of Runx1 function in vivo does not result in a change in the quantity of progenitors but leads to a decrease in precursor number and an increase in differentiated ORNs. These effects result in premature and ectopic ORN differentiation. Further, exogenous Runx1 expression in cultured olfactory neural progenitors causes an expansion of the mitotic cell population. In agreement with these findings, exogenous Runx1 expression also promotes cortical neural progenitor cell proliferation without inhibiting neuronal differentiation. These effects appear to involve transcriptional repression mechanisms. Consistent with this possibility, Runx1 represses transcription driven by the promoter of the cell cycle inhibitor p21Cip1 in cortical progenitors. Taken together, these findings suggest a previously unrecognized role for Runx1 in coordinating the proliferation and neuronal differentiation of selected populations of neural progenitors/precursors.Another significant step in the development of the mammalian nervous system is the acquisition of distinctive neuronal traits. This thesis also shows that Runx1 is expressed in selected populations of postmitotic neurons of the murine embryonic central and peripheral nervous systems. In embryos lacking Runx1 activity, hindbrain branchiovisceral motor neuron precursors of the cholinergie lineage are correctly specified but then fail to enter successive stages of differentiation and undergo increased cell death resulting in neuronal loss in the mantle layer. Runx1 inactivation also leads to a loss of selected sensory neurons in trigeminal and vestibulocochlear ganglia. These findings uncover previously unrecognized roles for Runx1 in the regulation of neuronal subtype specification.
This thesis thus presents a novel factor which functions at several steps in the development of the mammalian nervous system and adds to the growing body of work on the processes involved in elaborating such a complex and vital structure.
5
Barutcu, Ahmet Rasim. "Characterization of Higher-order Chromatin Structure in Bone Differentiation and Breast Cancer: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/827.
Full textAbstract:
Higher-order genome organization is important for the regulation of gene expression by bringing different cis-regulatory elements and promoters in proximity. The establishment and maintenance of long-range chromatin interactions occur in response to cellular and environmental cues with the binding of transcription factors and chromatin modifiers. Understanding the organization of the nucleus in differentiation and cancer has been a long standing challenge and is still not well-understood. In this thesis, I explore the dynamic changes in the higher-order chromatin structure in bone differentiation and breast cancer. First, we show dynamic chromatin contact between a distal regulatory element and the promoter of Runx2 gene, which encodes the Runtrelated transcription factor 2 (RUNX2) that is essential for bone development. Next, via using a genome-wide approach, we show that breast cancer cells have altered long-range chromatin contacts among small, gene-rich chromosomes and at telomeres when compared with mammary epithelial cells. Furthermore, we assess the changes in nuclear structure and gene expression of breast cancer cells following Runt-related transcription factor 1 (RUNX1) deficiency, an event frequently observed in breast cancer. Finally, I present the role of the central ATPase subunit of the SWI/SNF complex, SMARCA4 (BRG1), in mediating nuclear structure and gene expression. Taken together, the research presented in this thesis reveals novel insight and paradigm for the dynamic changes in disease and differentiation, as well as uncovers previously unidentified roles for two chromatin regulatory proteins, RUNX1 and SMARCA4.
6
Young, Daniel W. "Regulation of Cell Growth and Differentiation within the Context of Nuclear Architecture by the Runx2 Transcription Factor: a Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/19.
Full textAbstract:
The Runx family of transcription factors performs an essential role in animal development by controlling gene expression programs that mediate cell proliferation, growth and differentiation. The work described in this thesis is concerned with understanding mechanisms by which Runx proteins support this program of gene expression within the architectural context of the mammalian cell nucleus. Multiple aspects of nuclear architecture are influenced by Runx2 proteins including sequence-specific DNA binding at gene regulatory regions, organization of promoter chromatin structure, and higher-order compartmentalization of proteins in nuclear foci. This work provides evidence for several functional activities of Runx2 in relation to architectural parameters of gene. expression for the control of cell growth and differentiation. First, the coordination of SWI/SNF mediated chromatin alterations by Runx2 proteins is found to be a critical component of osteoblast differentiation for skeletal development. Several chromatin modifying enzymes and signaling factors interact with the developmentally essential Runx2 C-terminus. A patent-pending microscopic image analysis strategy invented as part of this thesis work - called intranuclear informatics - has contributed to defining the C-terminal portion of Runx2 as a molecular determinant for the nuclear organization of Runx2 foci and directly links Runx2 function with its organization in the nucleus. Intranuclear informatics also led to the discovery that nuclear organization of Runx2 foci is equivalently restored in progeny cells following mitotic division - a natural perturbation in nuclear structure and function. Additional microscopic studies revealed the sequential and selective reorganization of transcriptional regulators and RNA processing factors during progression of cell division to render progeny cells equivalently competent to support Runx2 mediated gene expression. Molecular studies provide evidence that the Runx proteins have an active role in retaining phenotype by interacting with target gene promoters through sequence-specific DNA binding during cell division to support lineage-specific control of transcriptional programs in progeny cells. Immunolocalization of Runx2 foci on mitotic chromosome spreads revealed several large foci with pairwise symmetry on sister chromatids; these foci co-localize with the RNA polymerase I transcription factor, Upstream Binding Factor (UBFl) at nucleolar organizing regions. A series of experiments were carried out to reveal that Runx2 interacts directly with ribosomal DNA loci in a cell cycle dependent manner; that Runx2 is localized to UBF foci within nucleoli during interphase; that Runx2 attenuates rRNA synthesis; and that this repression of ribosomal gene expression by Runx2 is associated with cell growth inhibition and induction of osteoblast-specific gene expression. This thesis has identified multiple novel mechanisms by which Runx2 proteins function within the hierarchy of nuclear architecture to control cell proliferation, growth and differentiation.
7
Byon, Chang Hyun. "Oxidative stress-stimulated vascular calcification." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2010r/byon.pdf.
Full text
8
Ko, Rose Marie. "The effect of the AML1-ETO translocation on cell cycle tumor suppressor gene function." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2008r/ko.pdf.
Full text
9
Gutierrez, Gallegos Soraya Elisa. "Mechanisms Contributing to Transcriptional Regulation and Chromatin Remodeling of the Bone Specific Osteocalcin Gene." eScholarship@UMMS, 2002. https://escholarship.umassmed.edu/gsbs_diss/12.
Full textAbstract:
Activation of tissue-specific genes is a tightly controlled process that normally involves the combined action of several transcription factors and transcriptional co-regulators. The bone-specific osteoca1cin gene (OC) has been used as a prototype to study both tissue-specific and hormonal responsiveness. In this study we have examined the role of Runx2, VDR and C/EBP factors in the regulation of OC gene transcription. Contributions of the Runx and VDRE motifs to OC promoter activity were addressed by introducing point mutations within the context of the rat (-1.1 kb) osteocalcin promoter fused to a CAT-reporter gene. The functional significance of these mutations was assayed following transient transfection and after genomic integration in ROS 17/2.8 osteoblastic cell lines. Furthermore, we tested the effect of these mutations on the chromatin organization of the OC promoter. Our data show that all three Runx sites are required for maximal activation of the OC promoter and that the distal sites contribute significantly to the basal activity. Strikingly, mutation of the three Runx sites abrogates responsiveness of the OC promoter to vitamin D; this loss is also observed when only the Runx sites flanking the VDRE are mutated. Chromatin changes that result in the appearance of DNase I hypersensitive sites during activation of the OC gene are well documented. Mutation of the three Runx sites results in altered chromatin structure as reflected by absence of DNase I hypersensitive sites at the vitamin D response element and over the proximal, tissue-specific basal promoter. These data are consistent with the critical role of Runx2 in osteoblast maturation and bone development.
Mutation of the VDRE resulted in a complete loss of vitamin D responsiveness; however, this mutant promoter exhibited increased basal activity. The two DNase I hypersensitive sites characteristic of the transcriptionally active OC gene in osteoblastics cells were not altered upon mutation of the VDRE element, although restriction enzyme accessibility in the proximal promoter region was decreased. We also found an increased level of histone H3 acetylation at the VDRE mutant promoter in comparison to the endogenous gene. Thus binding of VDR to OC promoter is required to achieve a normal transcriptional regulation and chromatin structure of the OC gene.
Although Runx2 is considered a master gene for bone development and osteoblast differentiation, it is noteworthy that osteoblast-specific transcription of the rat OC promoter occurs even in the absence of Runx sites. Therefore, other transcription factor(s) should be able to drive OC expression. We characterized a C/EBP enhancer element in the proximal promoter of the rat osteoca1cin gene that resides in close proximity to a Runx element, essential for tissue-specific activation. We find that C/EBPβ or δ and Runx2 factors interact together in a synergistic manner to enhance OC transcription in cell culture systems. Mutational analysis demonstrated that this synergism is mediated through the C/EBP responsive element in the OC promoter and requires a direct interaction between Runx2 and C/EBPβ or δ.
Taken together, our findings strongly support a mechanism in which combinatorial interaction of Runx2, VDR, C/EBPβ or δ and probably other transcription factors are needed for regulating OC expression. In this process Runx factors not only act as simple transcriptional trans activators but also by facilitating modifications in promoter architecture and maintaining an active conformation of the target gene promoter.
10
Dowdy, Christopher R. "Runx1 C-terminal Domains During Hematopoietic Development and Leukemogenesis: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/604.
Full textAbstract:
Runx1 is a master regulator of hematopoiesis, required for the initiation of definitive hematopoiesis in the embryo and essential for appropriate differentiation of many hematopoietic lineages in the adult. The roles of Runx1 in normal hematopoiesis are juxtaposed with the high frequency of Runx1 mutations and translocations in leukemia. Leukemia associated Runx1 mutations that retain DNA-binding ability have truncations or frame shifts that lose C-terminal domains. These domains are important for subnuclear localization of Runx1 and protein interactions with co-factors. The majority of leukemia associated Runx1 translocations also replace the C-terminus of Runx1 with chimeric fusion proteins. The common loss of Runx1 C-terminal domains in hematopoietic diseases suggests a possible common mechanism. We developed a panel of mutations to test the functions of these domains in vitro, and then developed mouse models to examine the consequences of losing Runx1 C-terminal domains on hematopoietic development and leukemogenesis in vivo.
We previously observed that overexpression of a subnuclear targeting defective mutant of Runx1 in a myeloid progenitor cell line blocks differentiation. Gene expression analysis before differentiation was initiated revealed that the mutant Runx1 was already deregulating genes important for maturation. Furthermore, promoters of the suppressed genes were enriched for binding sites of known Runx1 co-factors, indicating a non-DNA-binding role for the mutant Runx1.
To investigate the in vivo function of Runx1 C-terminal domains, we generated two knock-in mouse models; a C-terminal truncation, Runx1Q307X, and a point mutant in the subnuclear targeting domain, Runx1 HTY350-352AAA . Embryos homozygous for Runx1 Q307X phenocopy a complete Runx1 null and die in utero from central nervous system hemorrhage and lack of definitive hematopoiesis. Embryos homozygous for the point mutation Runx1HTY350-352AAA bypass embryonic lethality, but have hypomorphic Runx1 function. Runx1HTY350-352AAA results in defective growth control of hematopoietic progenitors, deregulation of B-lymphoid and myeloid lineages, as well as maturation delays in megakaryocytic and erythroid development.
Runx1 localizes to subnuclear domains to scaffold regulatory machinery for control of gene expression. This work supports the role of transcription factors interacting with nuclear architecture for greater biological control, and shows how even subtle alterations in that ability could have profound effects on normal biological function and gene regulation.
Book chapters on the topic "Core Binding Factor Alpha 3 Subunit"
1
"Core-Binding Factor Subunit Alpha-3." In Encyclopedia of Signaling Molecules, 1198. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_100819.
Full text
2
"Core-Binding Factor, Runt Domain, Alpha Subunit 3." In Encyclopedia of Signaling Molecules, 1198. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_100820.
Full text