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Journal articles on the topic "SETBP1"
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Nguyen, Nhu, Kristbjorn Orri Gudmundsson, Anthony R. Soltis, et al. "Recruitment of MLL1 Complex Is Essential for SETBP1 to Induce Myeloid Transformation." Blood 138, Supplement 1 (2021): 1147. http://dx.doi.org/10.1182/blood-2021-152825.
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Abstract Abnormal activation of SETBP1 due to overexpression or missense mutations occurs frequently in various myeloid neoplasms and associates with poor prognosis. Direct activation of Hoxa9/Hoxa10/Myb transcription by SETBP1 and its missense mutants is essential for their transforming capability; however, the underlying mechanisms for such activation remain elusive. We found that knockdown of Mll1 in mouse myeloid progenitors immortalized by SETBP1 or its missense mutant SETBP1(D/N) caused significant reduction in the mRNA levels of Hoxa9/Hoxa10/Myb, suggesting that Mll1 is critical for their transcriptional activation induced by SETBP1 and its missense mutants. Physical association of MLL1 with SETBP1/SETBP1(D/N) was readily detected by co-immunoprecipitation in nuclear extracts of these cells, further suggesting that they may form a complex in myeloid cells to activate transcription. This complex formation is likely mediated by direct interactions between SETBP1/SETBP1(D/N) and MLL1 as both SETBP1 and SETBP1(D/N) are capable of interacting with multiple regions of MLL1 in binding assays using proteins synthesized by in vitro transcription and translation. To better understand the extent of SETBP1/SETBP1(D/N)-MLL1 interaction in regulating gene transcription, we carried out both ChIP-seq and RNA-seq analysis in mouse Lin -Sca-1 +c-Kit + (LSK) cells transduced by pMYs retrovirus expressing SETBP1 or SETBP1(D/N) or empty pMYs virus. These analyses revealed extensive overlap in genomic occupancy for MLL1 and SETBP1/SETBP1(D/N) and their cooperation in activating many oncogenic transcription factor genes in addition to Hoxa9/Hoxa10/Myb, including additional HoxA genes (Hoxa1, Hoxa3, Hoxa5, Hoxa6, and Hoxa7), Myc, Eya1, Mef2c, Meis1, Sox4, Mecom, and Lmo2. A large group of ribosomal protein genes were also found to be directly activated by MLL1 and SETBP1/SETBP1(D/N), identifying ribosomal biogenesis as another significant pathway induced by their cooperation. To further assess the requirement for MLL1 in SETBP1-induced transformation using a genetic approach, we also generated SETBP1/SETBP1(D/N)-induced immortalized myeloid progenitors and AMLs using LSK cells from Mll1 conditional knockout mice. Mll1 deletion in immortalized progenitors significantly decreased SETBP1/SETBP1(D/N)-induced transcriptional activation and their colony-forming potential. More importantly, Mll1 deletion significantly extended the survival of mice transplanted with SETBP1/SETBP1(D/N)-induced AMLs, indicating that Mll1 is essential for the maintenance of such leukemias in vivo. We further found that pharmacological inhibition of MLL1 complex using a WDR5 inhibitor OICR-9429 efficiently abrogated SETBP1/SETBP1(D/N)-induced transcriptional activation and transformation. Thus, MLL1 complex plays a critical role in Setbp1-induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with SETBP1 activation. Disclosures Maciejewski: Novartis: Consultancy; Regeneron: Consultancy; Alexion: Consultancy; Bristol Myers Squibb/Celgene: Consultancy.
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Pacharne, Suruchi, Oliver M. Dovey, Jonathan L. Cooper, et al. "SETBP1 overexpression acts in the place of class-defining mutations to drive FLT3-ITD–mutant AML." Blood Advances 5, no. 9 (2021): 2412–25. http://dx.doi.org/10.1182/bloodadvances.2020003443.
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Abstract Advances in cancer genomics have revealed genomic classes of acute myeloid leukemia (AML) characterized by class-defining mutations, such as chimeric fusion genes or in genes such as NPM1, MLL, and CEBPA. These class-defining mutations frequently synergize with internal tandem duplications in FLT3 (FLT3-ITDs) to drive leukemogenesis. However, ∼20% of FLT3-ITD–positive AMLs bare no class-defining mutations, and mechanisms of leukemic transformation in these cases are unknown. To identify pathways that drive FLT3-ITD mutant AML in the absence of class-defining mutations, we performed an insertional mutagenesis (IM) screening in Flt3-ITD mice, using Sleeping Beauty transposons. All mice developed acute leukemia (predominantly AML) after a median of 73 days. Analysis of transposon insertions in 38 samples from Flt3-ITD/IM leukemic mice identified recurrent integrations at 22 loci, including Setbp1 (20/38), Ets1 (11/38), Ash1l (8/38), Notch1 (8/38), Erg (7/38), and Runx1 (5/38). Insertions at Setbp1 led exclusively to AML and activated a transcriptional program similar, but not identical, to those of NPM1-mutant and MLL-rearranged AMLs. Guide RNA targeting of Setbp1 was highly detrimental to Flt3ITD/+/Setbp1IM+, but not to Flt3ITD/+/Npm1cA/+, AMLs. Also, analysis of RNA-sequencing data from hundreds of human AMLs revealed that SETBP1 expression is significantly higher in FLT3-ITD AMLs lacking class-defining mutations. These findings propose that SETBP1 overexpression collaborates with FLT3-ITD to drive a subtype of human AML. To identify genetic vulnerabilities of these AMLs, we performed genome-wide CRISPR-Cas9 screening in Flt3ITD/+/Setbp1IM+ AMLs and identified potential therapeutic targets, including Kdm1a, Brd3, Ezh2, and Hmgcr. Our study gives new insights into epigenetic pathways that can drive AMLs lacking class-defining mutations and proposes therapeutic approaches against such cases.
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Kawashima, Nozomu, Yusuke Okuno, Yuko Sekiya, et al. "Generation of Cell Lines Harboring SETBP1 Mutations By the Crispr/Cas9 System." Blood 124, no. 21 (2014): 4622. http://dx.doi.org/10.1182/blood.v124.21.4622.4622.
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Abstract Introduction Recent advances in cancer genetics have led to the identification of somatic mutations in SET-binding protein 1 (SETBP1) in myeloid malignancies categorized as myeloproliferative neoplasm (MPN) and myelodysplastic syndromes (MDS). Heterozygous point mutations in SETBP1 are essentially found at a genomic level in myeloid malignancies, and the frequency of the mutated allele in cDNA suggests somatic heterozygosity without substantial imbalance in allelic expression. Thus, mutant SETBP1 presumably has a dominant altered biological activity. Most mutations in SETBP1 are located in the SKI homologous region. This region is suggested to include regions critical for ubiquitin binding and SETBP1 degradation. SETBP1 binds to SET, which protects against protease cleavage, and thus may result in PP2A inhibition and cell proliferation. Overexpression of SETBP1 resulting from a p.G870S alteration showed higher levels of the protein compared with wild-type (WT), indicating a prolonged halftime of SETBP1, which led to reduced PP2A activity and a higher cell proliferation rate. To date, however, our molecular biological understanding of SETBP1 mutations has been obtained only through observations of exogenous overexpression in cell lines. This may result in bias, considering the predicted dominant-negative function of SETBP1 mutations. Therefore, we used an RNA-guided endonuclease (RGEN), the CRISPR/Cas9 system, to generate a cell line harboring point mutations resulting in only relevant single amino acid substitutions in SETBP1. We analyzed cell signaling using the cell line thus established. Methods pSpCas9(BB) (PX330) was used to express humanized S. pyogenes Cas9 and gRNAs of interest. The gRNAs were designed by searching for NGG protospacer adjacent motif (PAM) sequences near the point mutation target sites. The candidate gRNAs were gRNA#1, 5′-TAGGGAGCCAATCTCGCAC-3′; gRNA#2, 5′-TGTCCCAATGCCGCTGTCGC-3′; gRNA#4, 5′-GTCCCAATGCCGCTGTCGCT-3′; and gRNA#7, 5′-GAGACGATCCCCAGCGACAG-3′. pCAG-EGxxFP harboring the 500 bp target region of WT SETBP1 was constructed for gRNA selection. For homology-dependent repair (HDR), we synthesized 70 mer single-stranded oligonucleotides (ssODN) having both the SETBP1 c.2602G>A, p.D868N mutation and synonymous mutation in the PAM. HEK293T cells were cultured in DMEM with 10% FBS. For cell signaling analysis, the cells were serum-depleted for 16 h prior to western blotting. Anti-SETBP1 antibody (ab98222), anti-phospho-Y307 PP2A antibody (E155), and anti phospho-p44/42 MAPK antibody (CST#4370) were used for cell signaling analysis. Results To validate an efficient sgRNA for DNA scission, we cotransfected pCAG-EGxxFP-SETBP1 and pSpCas9(BB)-SETBP1-gRNA plasmids into HEK293T cells. EGFP fluorescence, whose intensity is correlated with the efficacy of HDR, was observed 48 h later, and we determined that gRNA#2 was the most efficient. Next we cotransfected 293T cells with pCAG-EGxxFP-SETBP1, pSpCas9(BB)-SETBP1-gRNA#2, and ssODN for mutagenesis. Five days after transfection, single EGFP-positive clones were isolated using the FACSAria cell sorting system. Sanger sequencing confirmed that 293T cells harboring the SETBP1 p.D868N homozygous mutation were established. A clone with WT SETBP1 was also maintained as a control. To elucidate the effects of the SETBP1 mutation in 293T cells, we performed cell signaling analysis by western blotting. 293T-SETBP1 p.D868N cells showed higher levels of SETBP1 protein with lower molecular weight compared with WT, indicating a prolonged halftime, possibly due to loss of ubiquitination. In addition, 293T-SETBP1 p.D868N cells showed a higher phosphorylation level of PP2A (Y307, C subunit), a marker of PP2A inactivation. Finally, the phosphorylation level of p44/42 MAPK (ERK1/2) was increased in 293T-SETBP1 p.D868N cells. Conclusions We confirmed that the SETBP1 p.D868N mutation caused a prolonged halftime, resulting in PP2A inactivation and p44/42 MAPK activation in 293T cell lines. Our data suggest a potential therapy target for malignancies harboring SETBP1 mutations. More generally, this work illustrates the utility of RGEN technology for studying hematological malignancies. Disclosures No relevant conflicts of interest to declare.
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Pacharne, Suruchi, Oliver M. Dovey, Jonathan L. Cooper, et al. "Setbp1 Overexpression Acts in the Place of Class-Defining Somatic Mutations to Drive Mouse and Human FLT3-ITD-Mutant AMLs." Blood 136, Supplement 1 (2020): 31–32. http://dx.doi.org/10.1182/blood-2020-141743.
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Setbp1 overexpression acts in the place of class-defining somatic mutations to drive mouse and human FLT3-ITD-mutant AMLs Suruchi Pacharne,1,2 Oliver M. Dovey,1 Jonathan L. Cooper,1 Muxin Gu,1,2 MS Vijaybaskar,1,2 Mathias J. Friedrich,1,5 Malgorzata Gozdecka,1,2 Sandeep S. Rajan,1,4, Etienne De Braekeleer,1,2 Maxim Barenboim,5,6 Grace Collord,1,2 Hannes Ponstingl,1 Ruben Bautista,1 Milena Mazan,1,8 Roland Rad,5,6 Konstantinos Tzelepis,1,7 Penny Wright,3 and George S. Vassiliou1,2,9* Abstract Internal tandem duplications in FLT3 (FLT3-ITD) are found in 30% of acute myeloid leukemia (AML) cases and impart a poor prognosis. FLT3-ITD commonly synergizes with class-defining mutations such as chimeric fusion genes or mutations in NPM1, RUNX1, CEBPA or MLL to drive AML. However, 20% of FLT3-ITD-mutant AMLs bare no class-defining mutations and the mechanisms of acute leukemic transformation in these cases are unknown. To identify pathways that can drive FLT3-ITD-mutant AML in the absence of class-defining mutations, we performed an insertional mutagenesis (IM) screen in Flt3-ITD mice using the Sleeping Beauty transposon system, activated by the Mx1-Cre recombinase in hematopoietic stem cells. All mice developed acute leukemia, predominantly AML, after a median latency of 73 days (Figure A). Analysis of transposon insertions in 38 Flt3-ITD/IM leukemias identified common integration sites (CISs) in 22 loci (Figure B). The most commonly "hit" genes were Setbp1 (20/38), Ets1 (11/38), Ash1l (8/38), Notch1 (8/38), Erg (7/38), Flt3 (6/38) and Runx1 (5/38) (Figure B). Of these, Setbp1 and Runx1 were unique to Flt3-ITD and not identified as CISs in insertional mutagenesis screens of wild type, Npm1c or BCR-ABL-expressing mice. Transposon insertions in Setbp1, primarily located upstream of its first coding exon, were associated with Setbp1 and Hoxa mRNA overexpression and were invariably associated with AML development (Figure B). These findings propose that overexpression of wild type SETBP1 may collaborate with FLT3-ITD to drive leukemogenesis in human AMLs lacking mutations known to collaborate with mutant FLT3. Corroborating this, we found that SETBP1 expression was higher in human FLT3-ITD-mutant AMLs lacking class-defining mutations and in those with RUNX1 mutations (Figure C). We go on to show that Setbp1 insertions activate a Hoxa gene signature such that shares significant similarities, but also specific differences to those driven by mutant Npm1 and MLL fusion genes. We go on to show, using CRISPR-gRNA, that whilst Flt3ITD/+/SETBP1IM+AMLs are entirely dependent on Setbp1 expression, Flt3ITD/+/Npm1cA/+AMLs are not, but do depend on the expression of the homebox gene Nkx2.3. Our findings propose that SETBP1 overexpression activates a gene expression pattern that collaborates with FLT3-ITD to drive many human AMLs and that this combination represents a specific subtype of AML amongst AMLs lacking class-defining mutations. To identify genetic vulnerabilities of this AML subtype, we performed genome-wide CRISPR-Cas9 recessive screens in primary murine Flt3ITD/+SETBP1IM+AMLs and identified more than 2000 genetic vulnerabilities, of which 677 were not required for the survival of HPC7 non-leukemic hematopoietic cells including >100 "druggable" genes such as Brd3, Ezh2 and Hmgcr (Figure D). Collectively our study: i) identifies SETBP1overexpression as a non-genetic alteration driving a subgroup of FLT3-ITD mutant AMLs lacking class-defining somatic mutations and ii) goes on to define the genetic vulnerabilities of such AMLs as a starting point for the development of targeted therapies. Figure Disclosures Vassiliou: Kymab Ltd - Monoclonal antibody company. Currently not working in myeloid cancers or clonal haematopoiesis.: Consultancy.
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Oakley, Kevin, Yufen Han, Bandana A. Vishwakarma, et al. "Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10." Blood 119, no. 25 (2012): 6099–108. http://dx.doi.org/10.1182/blood-2011-10-388710.
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Abstract Acquisition of self-renewal capability by myeloid progenitors to become leukemic stem cells during myeloid leukemia development is poorly understood. Here, we show that Setbp1 overexpression efficiently confers self-renewal capability to myeloid progenitors in vitro, causing their immortalization in the presence of stem cell factor and IL-3. Self-renewal after immortalization requires continuous Setbp1 expression. We also found that Hoxa9 and Hoxa10 mRNA are present at dramatically higher levels in Setbp1-immortalized cells compared with other immortalized cells, and are induced shortly after Setbp1 expression in primary myeloid progenitors. Suppression of either gene in Setbp1-immortalized cells drastically reduces their colony-forming capability. Interestingly, Setbp1 protein associates with Hoxa9 and Hoxa10 promoters in chromatin immunoprecipitation assays in these cells, suggesting that both are direct transcriptional targets of Setbp1. Setbp1 also promotes self-renewal of myeloid progenitors in vivo as its coexpression with BCR/ABL transforms primary mouse myeloid progenitors, generating aggressive leukemias in recipient mice resembling chronic myelogenous leukemia (CML) myeloid blast crisis. Increased SETBP1 mRNA levels were also detected in a subset of CML advanced phase/blast crisis patients with high levels of HOXA9 and HOXA10 expression. Thus, Setbp1 activation represents a novel mechanism conferring self-renewal capability to myeloid progenitors in myeloid leukemia development.
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Makishima, Hideki, Kenichi Yoshida, Nhu Nguyen, et al. "Somatic Mutations in Schinzel-Giedion Syndrome Gene SETBP1 Determine Progression in Myeloid Malignancies." Blood 120, no. 21 (2012): 2. http://dx.doi.org/10.1182/blood.v120.21.2.2.
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Abstract Abstract 2 MDS and other chronic myeloid malignancies such as MDS/MPN are characterized by a frequent progression to secondary AML (sAML), a likely multistep process of acquisition of genetic abnormalities. Genes involved in congenital genetic cancer susceptibility syndromes are often targets of somatic mutations in various tumors. For instance, germ-line mutations of SETBP1 are associated with Schinzel-Giedion syndrome (SGS), which is characterized by skeletal malformations, mental retardation and frequent neuroepithelial tumors. While SETBP1 overexpression in myeloid malignancies links to poor prognosis, somatic mutations of SETBP1 were not previously identified in leukemias. When we performed whole exome sequencing of 20 cases with myeloid malignancies, in addition to detecting previously described lesions, such as TET2, CBL and ASXL1, we identified a somatic SETBP1 mutation (D868N) in 2 cases with RAEB. Analysis of DNA from CD3+ cells from these patients confirmed its somatic nature. Sanger sequencing was applied to all coding exons in an additional 48 cases, leading to detection of 2 additional somatic mutations (G870S and I871T) in 2 patients with CMML and sAML, respectively. These findings prompted us to further expand our screening cohort: targeted SETBP1 sequencing was performed in a total of 734 patients (283 with MDS, 106 with sAML, 167 with MDS/MPN, 138 MPN and 146 with primary AML): 52 mutations were detected in 52 patients (7.1%); D868N, G870S and I871T alterations were more frequently observed (N=27, N=16 and N=5, respectively), while D868Y, S869N, D880E and D880N were less prevalent. These mutations, of which 92% (48 out of 52) were identical to those in the SGS germ line, were detected in 15% with CMML (24/156), 15% with sAML (16/106) and 7% CML blast phase (2/28). Clinically, mutant cases were associated with higher age (p=.014), deletion of chromosome 7q (p=.0005) and shorter median survival (28 vs. 13 months, p<.0001). As shown in the analysis of 11 paired samples of progressing MDS patients, all SETBP1 mutations were acquired during leukemic evolution. In addition to mutations, SETBP1 overexpression can be found in 12% and 26% of cases of MDS and sAML, respectively, a finding linking higher activity of SETBP1 to leukemic progression. To directly test whether SETBP1 mutations represent gain-of-function, we performed retroviral transduction of murine Setbp1 engineered with two of the somatic mutations, D868N and I871T, and evaluated the ability of the mutants to immortalize normal murine myeloid progenitors. With a low viral titer of 1 x105 cfu, both Setbp1 mutants caused efficient immortalization of myeloid progenitors, similar to overexpressed WT Setbp1. In addition, cells immortalized with mutant Setbp1 proliferated faster than cells with WT Setbp1. These data suggest that mutations of SETBP1 in our study represent gain-of-function in leukemias. The in vitro immortalization effect of overexpressed WT Setbp1 was associated with and dependent on Hoxa9 and Hoxa10 overexpression. We performed quantitative RT-PCR and western blot experiments to evaluate expression of these genes in our mutant cases. Relative HOXA9 and HOXA10 mRNA expression values were higher in all mutant cases (N=7) than median of those in WT cases (N=4). Also, both HOXA9 and HOXA10 proteins were detected in all cases with SETBP1 mutations, suggesting that HOXA9 and HOXA10 induction is consistently associated with SETBP1 mutations similar to observations in forced expression of WT Setbp1. Moreover, in agreement with findings in primary cells showing that SETBP1 mutations or high SETBP1 expression share a common genetic association with RUNX1 mutations, Runx1 expression was reduced after in vitro immortalization of normal bone marrow cells by forced Setbp1 overexpression and two Runx1 promoter sequences were amplified after ChIP performed with antibody specific for exogenous Setbp1 protein. Moreover, Setbp1 shRNA knockdown resulted in enhanced Runx1 transcription consistent with the negative regulation of this gene by Setbp1. These results indicate that SETBP1 is associated with decreased activity of RUNX1 due to hypomorphic mutations or by direct down-modulation WT RUNX1 expression bypassing the need for mutations. In sum, somatic recurrent SETBP1 mutations are lead to gain of function and are associated with molecular pathogenesis of myeloid leukemic transformation of various primary myeloid subentities. Disclosures: Makishima: Scott Hamilton CARES Initiative: Research Funding. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding.
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Carratt, Sarah A., Zachary Schonrock, Theodore Braun, Cody Coblentz, Amy Foley, and Julia E. Maxson. "SETBP1 Mutations Accelerate NRAS-Mutant Leukemia." Blood 134, Supplement_1 (2019): 1254. http://dx.doi.org/10.1182/blood-2019-125125.
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Juvenile myelomonocytic leukemia (JMML) is an aggressive, rare form of early childhood leukemia driven by Ras pathway mutations. Mutations in SET binding protein 1 (SETBP1) are a strong predictor of relapse in JMML, and are associated with reduced five-year event-free survival. Although some mechanisms of oncogenesis have been established for SETBP1 mutations, it remains unclear why they are associated with poor prognosis and relapse. The goal of this study was to understand how SETBP1 modulates the biology of Ras-driven leukemias and to determine whether there are therapeutic vulnerabilities of SETBP1-JMML that can be exploited. Here, we present novel findings on the synergy of SETBP1 and NRAS, and provide pre-clinical evidence for therapeutic intervention. To address our central question of how SETBP1 mutations modulate Ras pathway-driven leukemia, we first set out to determine whether mutant SETBP1 promotes the growth of hematopoietic progenitors in the context of a Ras pathway mutation. To this end, we performed mouse hematopoietic colony forming unit assays in the absence of exogenous cytokines. Both NRAS-G12D and PTPN11-E76K alone formed a modest number of colonies, and the addition of SETBP1-D868N significantly augmented colony number with either Ras pathway mutation. The combination of NRAS-G12D and SETBP1-D868Nconfer robust serial replating, indicating that the SETBP1-D868N promotes oncogenic transformation and progenitor self-renewal in the NRAS-G12D mutant cells. To understand how SETBP1 modulates therapeutic response, a novel NRAS/SETBP1-mutant cell line was generated and analyzed with a chemical screen of essential cell growth and survival pathways. This screen revealed dependencies on the mTOR/AKT/PI3K and Raf/MEK/ERK pathways. An immunoblot analysis revealed that mutant SETBP1 enhanced NRAS-driven ERK and mTOR pathway activation. Inhibitors of these pathways, such as rapamycin and trametinib were highly efficacious against our cell line. The combination of trametinib and rapamycin had sub-nanomolar efficacy in our NRAS/SETBP1-hematopoietic cell line and exhibited greater than bliss additivity at several time points. To evaluate the efficacy in vivo, our SETBP1/NRAS-mutant cell line was injected into mice. At the onset of disease, mice were given once-daily treatment of trametinib, rapamycin, combination treatment, or DMSO control. The median survival of mice receiving DMSO was 19.5-days post-transplant, compared to 21 days for rapamycin, 35 days for the combination treatment, and 42 days for trametinib. Treatment with trametinib significantly increased the median survival to beyond rapamycin or DMSO, doubling the survival time of the mice. Our data demonstrates that SETBP1 mutations accelerate NRAS-driven oncogenesis and enhance MAPK pathway activation by NRAS-G12D. Despite enhanced transforming potential, SETBP1-mutant cells are still sensitive to inhibitors of the RAS/ERK/MAPK pathway. Trametinib, an inhibitor of this pathway, doubles overall survival in our murine model of NRAS/SETBP1-mutant leukemia, thus providing encouraging pre-clinical data for the use of trametinib in SETBP1-mutant disease. Disclosures No relevant conflicts of interest to declare.
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Carratt, Sarah A., Theodore P. Braun, Zachary Schonrock, et al. "Oncogenic SETBP1 Mutations Combine with Activating Mutations in CSF3R to Produce a Highly Proliferative, Lethal Leukemia through Aberrant Myc Signaling." Blood 136, Supplement 1 (2020): 51–52. http://dx.doi.org/10.1182/blood-2020-143072.
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SETBP1 (SET Binding Protein 1) mutations are associated with exceptionally poor prognosis in myeloid neoplasms. Despite this, SETBP1's role in oncogenesis remains incompletely understood. In this study, we find that SETBP1 leads to a marked upregulation of the Myc oncogene and associated pro-stem and progenitor programs through epigenetic dysregulation. We further identify an epigenetic modulatory drug that normalizes SETBP1-driven Myc overexpression and synergizes with disease-relevant therapy. SETBP1 has documented roles in both the regulation of tumor suppressor pathways and modulation of transcription. To understand how SETBP1 modulates leukemia biology and leverage this mechanistic insight to develop novel therapeutic strategies, we turned to a genetically well-defined model system, chronic neutrophilic leukemia (CNL). SETBP1 is mutated in approximately half of all cases of CNL, a myeloproliferative neoplasm characterized by the presence of signaling-activating mutations in Colony Stimulating Factor 3 Receptor (CSF3R). By expressing SETBP1 and CSF3R mutations in mouse hematopoietic progenitors, we have generated models of CNL that can be leveraged for mechanistic studies and drug development. In a hematopoietic colony forming unit (CFU) assay, murine hematopoietic progenitors co-expressing mutant SETBP1 and mutant CSF3R have a high proliferation phenotype compared to those with mutant CSF3R alone. When cells co-expressing mutant SETBP1 and CSF3R are transplanted into lethally irradiated mice, they develop a rapidly lethal disease relative to the control mice. This is associated with an expansion of the granulocyte lineage, quantified by complete blood count, flow cytometry and histology. We find that SETBP1 is essential for the induction of a pro-proliferative transcriptional program. One of the most prominent SETBP1-associated signatures is that of Myc target genes. Myc itself is one of the top differentially expressed genes driven by SETBP1. Congruent with its increased expression, we also find higher Myc transcriptional activity in cells overexpressing SETBP1. To better understand the epigenetic regulation of Myc and progenitor pathways by SETBP1, we employed a low input profiling methods called CUT&Tag to assess the activation of regulatory elements. We began by profiling two epigenetic marks associated with active enhancers-H3K4me1 and H3K27Ac. We also assessed activation of the Myc promoter by measuring H3K27Ac and H3K4me3. Together this data helps us to understand the epigenetic underpinnings for dysregulation of Myc-driven programs by SETBP1. Therapeutic strategies that normalize aberrant Myc activity may be effective against SETBP1-driven disease. We found that SETBP1 and CSF3R transformed hematopoietic progenitors are highly sensitive to inhibitors of the epigenetic regulator lysine specific demethylase 1 (LSD1). LSD1 inhibition restores Myc expression to physiological levels and represses Myc promotor activity in vitro. Furthermore, LSD1 inhibitors are highly synergistic with JAK inhibitors, which block signaling downstream of CSF3R. Together these data establish the importance of Myc activation in SETBP1-driven malignancies and identify a therapeutic approach to normalize aberrant Myc activity. In future, we will use the insight gained in this genetically well defined disease to inform studies on the mechanistic basis and therapeutic vulnerabilities of other SETBP1-mutant myeloid malignancies. Disclosures Maxson: Gilead Sciences: Research Funding; Ionis Pharmaceuticals: Other: Joint oversight committee for a collaboration between OHSU and Ionis Pharmaceuticals.
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Wakamatsu, Manabu, Hideki Muramatsu, Norihiro Murakami, et al. "Detection of Subclonal SETBP1 and JAK3 Mutations in Patients with Juvenile Myelomonocytic Leukemia Using Droplet Digital PCR." Blood 134, Supplement_1 (2019): 4213. http://dx.doi.org/10.1182/blood-2019-125354.
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Background Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myelodysplastic/myeloproliferative disease. Approximately 85% of patients with JMML harbor germline and/or somatic mutations in RAS pathway genes, such as PTPN11, NF1, CBL, NRAS, and KRAS. In a subset of patients with JMML, SETBP1 and JAK3 mutations were identified as secondary mutations in addition to primary RAS mutations. These secondary mutations are associated with the disease progression and poor clinical outcome. Recently, it has been reported that subclonal SETBP1 mutation also correlates with a dismal prognosis. Therefore, we hypothesized that subclonal JAK3 mutation is present in a higher than expected number of patients with JMML and associated with poor prognosis. The aim of this study is to identify patients with subclonal SETBP1 and/or JAK3 mutations at the diagnosis using droplet digital PCR (ddPCR) and to elucidate their clinical outcomes. Patients and Methods We enrolled 128 patients with JMML and 15 with Noonan syndrome-associated myeloproliferative disorder (NS/MPD). Using bone marrow (BM) or peripheral blood derived genomic DNA, ddPCR was performed in the 143 patients to detect SETBP1 p.D868N and JAK3 p.R657Q hotspot mutations with low variant allele frequencies (VAF). The study was approved by the institutional review board of Nagoya University Graduate School of Medicine. Results To assess the false-positive rate of the ddPCR assay for each mutation, the assay was also performed in 30 healthy volunteers. Among these, the false-positive rate (mean ± standard deviation) for SETBP1 and JAK3 mutations was 0.010% ± 0.010% and 0.013% ± 0.012%, respectively. Due to the presence of false-positive droplets, the sensitivity and the quantitative linearity was evaluated for >0.01% VAF. The significant correlation between the expected and the observed VAF in SETBP1 and JAK3 was observed (R-squared, 0.9923 and 0.9922, respectively). Therefore, 0.05% VAF was defined as the cut-off value in this assay. Among the 143 patients, ddPCR detected SETBP1 and JAK3 mutations in nine (6.3%) and fifteen (10.5%), respectively. SETBP1 and JAK3 mutations, including variants with low allele frequencies, were not detected in NS/MPD. Among patients with SETBP1 and/or JAK3 mutations, two and six patients harbored less than 1.0% VAF. Patients with less than 1.0% VAF in SETBP1 or JAK3 mutation exhibited a significantly poorer 2-year transplantation-free survival than those without SETBP1 and JAK3 mutations (P = 3.05 × 10-3). JMML is genetically characterized by an extremely small number of somatic mutations (an average of 0.8 mutations/exome/patient). However, we demonstrated that among 19 patients with SETBP1 and/or JAK3 mutations, five patients (26.3%) harbored both the mutations. This finding suggested a statistically significant co-occurrence of SETBP1 and JAK3 mutations in JMML. In order to determine whether SETBP1 and JAK3 mutations were present in the same clone or not, we performed colony formation assays using BM cells in one of the five patients with both SETBP1 and JAK3 mutations. This case harbored 0.9% VAF in JAK3 and 41.9% in SETBP1 in addition to 46.0% in PTPN11 mutation (c.227A>C, p.E76A), respectively. In total, 93 colonies were collected and individually analyzed by Sanger sequencing, of which two colonies (2.1%) were identified with both SETBP1 and JAK3 mutations. Conclusions ddPCR is a useful tool to assess subclonal SETBP1 and JAK3 hotspot mutations and to estimate the prognosis. It would be better to start preparing for hematopoietic stem cell transplantation when patients with JMML harbored subclonal SETBP1 and/or JAK3 mutations at the diagnosis. While JMML is characterized by a paucity of somatic mutations, clones harboring SETBP1 and JAK3 mutations were identified. This finding suggests that SETBP1 and JAK3 mutation are susceptible to each other. Furthermore, the serial acquisition of SETBP1 and JAK3 mutations might correlate with the disease progression. Disclosures No relevant conflicts of interest to declare.
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Cristóbal, Ion, Francisco J. Blanco, Laura Garcia-Orti, et al. "SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia." Blood 115, no. 3 (2010): 615–25. http://dx.doi.org/10.1182/blood-2009-06-227363.
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Abstract Acute myeloid leukemias (AMLs) result from multiple genetic alterations in hematopoietic stem cells. We describe a novel t(12;18)(p13;q12) involving ETV6 in a patient with AML. The translocation resulted in overexpression of SETBP1 (18q12), located close to the breakpoint. Overexpression of SETBP1 through retroviral insertion has been reported to confer growth advantage in hematopoietic progenitor cells. We show that SETBP1 overexpression protects SET from protease cleavage, increasing the amount of full-length SET protein and leading to the formation of a SETBP1–SET-PP2A complex that results in PP2A inhibition, promoting proliferation of the leukemic cells. The prevalence of SETBP1 overexpression in AML at diagnosis (n = 192) was 27.6% and was associated with unfavorable cytogenetic prognostic group, monosomy 7, and EVI1 overexpression (P < .01). Patients with SETBP1 overexpression had a significantly shorter overall survival, and the prognosis impact was remarkably poor in patients older than 60 years in both overall survival (P = .015) and event-free survival (P = .015). In summary, our data show a novel leukemogenic mechanism through SETBP1 overexpression; moreover, multivariate analysis confirms the negative prognostic impact of SETBP1 overexpression in AML, especially in elderly patients, where it could be used as a predictive factor in any future clinical trials with PP2A activators.
Dissertations / Theses on the topic "SETBP1"
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VALLETTA, SIMONA. "Recurrent SETBP1 mutations in atypical chronic myeloid leukemia." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/50227.
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Atypical chronic myeloid leukemia (aCML) is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes. aCML shares clinical and laboratory features with Chronic Myeloid Leukemia (CML), but it lacks the Philadelphia chromosome and the resulting BCR-ABL fusion gene. This crucial difference with CML points to a different pathogenetic process. Because no specific recurrent genomic or karyotypic abnormalities have been identified in aCML, and the molecular pathogenesis of this disease has remained elusive with a dismal outcome, we performed exome-sequencing of eight aCML patients, in order to identify new possible recurrent mutations. The presence of an identical mutation not previously involved in cancer in two different aCML cases altering SETBP1 gene, prompted us to resequence this particular gene in samples from additional subjects with aCML or other hematological malignancies and in cell lines representative of the most common human solid cancers. SETBP1 mutations were identified only in aCML and in the closely related disorders and represents the first gene shown to be enriched and recurrently mutated in aCML. Most SETBP1 mutations were located between codons 858 and 871 causing abrogation of a degron binding site for E3-ubiquitin β-TrCP1 and protection from proteasomal degradation. This causes accumulation of SETBP1 and SET protein, decreased PP2A phosphatase activity and higher proliferation rates. Individuals with SETBP1 mutations had higher white blood cell counts and worse prognosis, indicating SETBP1 as a possible valuable diagnostic tool in the differential diagnosis of MDS/MPN syndromes and their prognosis.
This study increases the knowledge of the mechanisms by which malignancy arises and will have important consequences for the diagnosis, prognosis and treatment of aCML and diseases associated with SETBP1 alterations.
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PERONACI, MARCO. "Characterization of new oncogenes identified through NGS-based analysis of leukemias: SETBP1 and ETS2-ERG." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/144663.
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In the past years, the improvements in sequencing technology led to the development of “Next Generation Sequencing” (NGS) technologies. Several NGS approaches exist. Whole genome sequencing (WGS) and whole exome sequencing (WES) allow the identification of genomic alterations such as small insertions/deletions, point mutations and structural variants. Whole transcriptome sequencing (RNA-Seq) permits to quantify gene expression profiles and to detect alternative splicing and fusion transcripts. Recently, by using WES on atypical chronic myeloid leukemia (aCML) samples, our group identified recurrent mutations in SETBP1 gene; also, by using RNA-Seq on acute myeloid leukemia (AML), we identified a new fusion gene: ETS2-ERG. In aCML, SETBP1 mutations disrupt a degron binding site, leading to a decreased protein degradation. This leads to an increased amount of SETBP1 protein interacting with its natural ligand SET, which in turn acts inhibiting the protein phosphatase 2A (PP2A) oncosuppressor. Interestingly, the SETBP1 mutational cluster affected in aCML is highly conserved and the same mutations were also observed in the Schinzel-Giedion syndrome (SGS). However, the inhibition of the PP2A by SET, the only known interactor of SETBP1, does not explain the phenotype of SGS. To further characterize the role of SETBP1 protein, 293 Flp-In isogenic cellular models expressing the empty vector or the wild type (WT) or mutated (G870S) form of SETBP1 were established. In these models SETBP1 was fused with a V5 tag. Chromatin Immunoprecipitation sequencing experiments (Chip-Seq) performed against V5 confirmed the binding of SETBP1 to DNA, both for the WT and G870S forms. In addition, RNA-Seq experiments were performed. The comparison between Chip-Seq and RNA-Seq data has allowed us to identify 130 genes presenting both the binding of SETBP1 to their promoter region and transcriptional upregulation. Together these data suggest a role for SETBP1 as a transcriptional activator. Co-immunoprecipitation (Co-IP) experiments in transiently transfected HEK293T cells coupled with mass spectrometry (MS) analysis were performed to identify potential interactors of SETBP1. MS analysis led to the identification of the host cell factor 1 (HCF1), a component of the SET1/KMT2A COMPASS-like complex. Independent validation by western blot and fluorescence resonance energy transfer (FRET) confirmed the direct binding of HCF1 to SETBP1. Further independent experiments confirmed the Co-Ip of SET1/KMT2A and PHF8 with SETBP1. SET1/KMT2A is a core component of COMPASS-like complex and possesses H3K4 methyltransferase activity, whereas PHF8 possesses H4K20 demethylase activity. Both marks are associated with actively transcribed genes. Taken together, we have shown that SETBP1 protein is able to act as a transcriptional activator recruiting the HCF1/KMT2A/PHF8 complex.
In a previous study, comparing cytogenetic analysis and RNA-Seq to detect chromosomal abnormalities on AML patient samples, a new fusion between the ETS2 and ERG genes was reported. The patient carrying this fusion was affected by acute promyelocytic leukemia (APL) and did not respond to therapy with retinoic acid. The role of the ETS2-ERG fusion is not known. To gain insight about the functional role of ETS2-ERG fusion in APL two cellular models were established. HL-60 and NB-4 cells were stable transfected with retroviral empty vector or with a vector carrying the fusion gene. This vector also carries the GFP as a positive selection marker. HL-60 cells carrying the ETS2-ERG fusion treated with retinoic acid showed a decrease in the expression at membrane level of the differentiation marker CD11b. This suggests that the ETS2-ERG fusion is able to impair the differentiation of APL cells upon retinoic acid treatment. Further experiments are ongoing to confirm the data in the NB4 cellular model.
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KHANDELWAL, PRAVEEN. "Elucidating the oncogenic role of genetic events in BCR-ABL1 positive chronic myeloid leukemia." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2016. http://hdl.handle.net/10281/99449.
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In hematological myeloid malignancies the accumulation of oncogenic events plays a significant role in disease progression. Therefore, in this work, we studied (i) the mutational landscape in typical chronic myeloid leukemia (CML) patients and (ii) the neoplastic role of Setbp1 mutation in atypical chronic myeloid leukemia (aCML).
1) We evaluated somatic variants in CML patients by Next Generation Sequencing, to study the molecular pathogenesis of cancer. We conducted a mutational analysis on 23 chronic phase BCR-ABL1+ CML patients through exome and RNA sequencing performed on diagnosis samples. A total of 107 non-synonymous variants (range 0-11 per patient) were identified by setting a threshold of mutation frequency >25%, which corresponds to the presence of a heterozygous mutation in >50% of cells, assuming a pure tumoral sample. A positive correlation was observed between number of mutations and patient age, indicating that several events were passenger mutations, being immortalized by the neoplastic transformation. However, when using a newly in-house developed tool (Oncoscore) to weigh the oncogenic potential of each mutation, a significant correlation was observed between the Sokal score and Oncoscore by using linear model statistical analysis. In long term follow-up (>2 years), 21 CML patients achieved complete cytogenetic responses (CCyR) and 2 failed to achieve any cytogenetic response with tyrosine kinase inhibitors. These two patients showed an Oncoscore value of (165.4 ±27.2) which was significantly higher than the one (80.6 ±12.7) in the 21 responding patients. No fusions (other than BCR/ABL1) were identified by RNA Seq, and no chromosomal alterations were observed by using the CEQer software. In conclusion, CML patients at diagnosis carry genetic alterations additional to the BCR/ABL1 fusion, which could be relevant for response to treatment and progression of the disease.
2) We aimed to gain insights into the biological role of Setbp1 mutations found in aCML patients, by invivo genetic manipulation techniques. Recently, by NGS approach, we identified a recurrent SETBP1 missense mutation in aCML patients, associated with poor overall survival. The most frequent SETBP1 mutations identified in various MDS/MPN neoplasms were positioned at D868N, S869G, G870S and I871T. The same mutations identified in myeloid malignancies had previously been observed as de novo recurrent germline mutations responsible for Schinzel-Giedion syndrome. Unfortunately, the biological role of Setbp1 and its activity in leukemic transformation is not exactly known. Therefore, an improved understanding of the molecular mechanism is imperative. So, we applied genetic engineering to construct a conditional knock-in model for dissecting the role of leukemia transforming factors in heterozygous Setbp1G870S mice. For construction, 3 genomic fragments of Setbp1 intron 3 and exons 4 through 6 were subcloned into the conditional replacement vector pDELBOY-3X. The linearised vector was then transfected into murine ES cells. We are currently screening ES cells to identify a correctly targeted clone for blastocyst injection and transplantion into pseudo-pregnant mice. The 1st generation Setbp1WT/floxed mice will express wild type Setbp1 under the control of its endogenous promoter. Thereafter, the expression of Setbp1G870S would be induced in a conditional manner with Cre-mediated recombination. Depending on the type of promoter driving Cre recombinase expression, the mutant allele will be expressed either constitutively (germline) or somatically, and it will be possible to study the oncogenic effects of Setbp1G870S in specific tissues, or in all tissue/cells. Additionally, the molecular interactions and physiological pathways accountable for tumorigenesis and the clonal evolution pattern will be examined by implementing the molecular and functional genomic techniques, which help in better understanding of developing targeted therapies.
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Rediger, Daniel. "Minimizing production setups by optimizing the production setup." Connect to resource, 2006. http://hdl.handle.net/1811/6493.
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Thesis (Honors)--Ohio State University, 2006.<br>Title from first page of PDF file. Document formatted into pages: contains 9 p. Includes bibliographical references (p. ). Available online via Ohio State University's Knowledge Bank.
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Andersson, Joakim, and Jimmy Bertilsson. "SETUP TIME OPTIMIZATION." Thesis, Örebro universitet, Institutionen för naturvetenskap och teknik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-23661.
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Sammanfattning Emhart Glass AB är världsledande företag inom glasflasktillverkning. De konstruerar automatiserade maskiner som formar glasflaskor. I Sverige finns det två fabriker, en i Örebro och en i Sundsvall. I Örebro tillverkar man främst reservdelar och nya delar till maskinerna medan man i Sundsvall monterar ihop maskinerna. Det finns totalt 15 olika fabriker och kontor över världen med huvudkontor i schweiziska Cham. Eftersom Emhart Glass Örebro har för långa ställtider på några av deras maskiner ska det undersökas hur omställningsarbetet går till i dagsläget och hur omställningsarbetet skiljer sig åt mellan operatörerna. Det ska även undersökas om det finns några möjligheter till förbättringar samt om det i dagsläget finns något standardiserat sätt som operatören borde följa. Ett dokument som beskriver hur ställarbetet ska gå till kommer även att tas fram. Ett utmärkt verktyg för att förkorta ställtiderna i en produktion är SMED-Metoden. Filosofin bakom SMED är att man ska analysera och skilja på inre och yttre ställ. Med inre och yttre ställ menas de som endast kan utföras då maskinen är avstängd resp. de som kan utföras när maskinen är i drift. För att standardisera omställningsarbetet så att samtliga operatörer jobbar på liknande sätt så krävs det att man tar fram en dokumentation över hur arbetet ska gå till. Därför har checklistor tagits fram till operatören. "Checklista - Omställning.xls" är en checklista med syftet att man ska kunna bocka för vilka delar i förberedelserna man gjort inför kommande ställ. Den har tagits fram för att man enkelt ska kunna hålla reda på vilka delar man gjort om man blivit tvungen att jobba med maskinen emellan förberedelserna eller om man slutar sitt skift och lämnar delar av arbetet till nästa operatör. Om samtliga av dessa förbättringar införs kan man förvänta sig en ställtidsreducering på 20,5% vilket motsvarar ca 35min per ställ. Ignorerar man inkörningstiderna och endast kollar på riggningstider kan man se en förbättring på 36,4 %.<br>Abstract Emhart Glass Ltd is a world leader in glass bottle manufacturing. They design automated machines that shape glass bottles. In Sweden there are two factories, one in Örebro and one in Sundsvall. In Örebro they manufacture primarily spare parts and new parts for the machines while they in Sundsvall assemble the machines. There are a total of 15 factories and offices around the world with the headquarter located in Swiss Cham.Since Emhart Glass Örebro has long setup times on some of their machines. This is why we want to identify the current setup process and how the setup process differs between operators. We will also look at whether there are any opportunities for improvement to be made and if they have a standardized way to work. A document that describes how to setup work should be done will also be developed.An excellent tool to shorten the setup time in a production is the SMED method. The philosophy behind SMED is that you should analyze and separate the inner and outer activities. Inner and outer activities mean those activities which can only be performed when the machine is turned off, respectively those activities that can be performed when the machine is in operation. In order to standardize the adjustment process so that all operators are working in a similar way it's required that you make a documentation about how the work should be done. Therefore, checklists been developed to the operator. "Checklista - Omställning.xls" is a checklist with the purpose to be able to check which parts of the preparations they have made before the next setup work. It has been designed to be easy to keep track of what parts you have done if you had to work with the machine between the trial or if you quit your shift and leaving parts of the work to the next operator. If all of these improvements are implemented, we expect a set-up time reduction of 20.5% which corresponds to about 35min per set-up. By ignoring the running time and only check on the setup times, one can see an improvement of 36.4%.
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Bernardo, Heliudson de Oliveira. "Cosmological models from string theory setups /." São Paulo, 2019. http://hdl.handle.net/11449/183612.
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Orientador: Horatiu Nastase<br>Resumo: Nesta tese, discutimos três modelos cosmológicos que são baseados direta ou indiretamente em ideias advindas de teoria das cordas. Depois de uma revisão geral de cosmologia em teoria das cordas, um resumo de cosmologia e teoria das cordas é apresentado, com ênfase nos conceitos fundamentais e teóricos. Então descrevemos como o acoplamento camaleônico pode potencialmente afetar as predições de inflação cósmica com campo único, com tratamento cuidadoso dos modos de perturbação cosmológica adiabáticos e de entropia. Além disso uma nova abordagem para a dualidade-T em soluções cosmológicas de supergravidade bosônica é discutida no contexto de teoria dupla de campos. Por fim, propomos uma nova prescrição para o mapa holográfico em cosmologia que pode ser usado para conectar modelos fundamentais de cosmologia holográfica com outras abordagens fenomenológicas.<br>Doutor
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Yang, Yanchun Bulfin Robert L. "Knapsack problems with setup." Auburn, Ala., 2006. http://repo.lib.auburn.edu/2006%20Summer/Dissertations/YANG_YANCHUN_31.pdf.
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Apotsos, Alex. "Setup in the surfzone." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/42219.
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Thesis (Ph. D.)--Joint Program in Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Dept. of Civil and Environmental Engineering; and the Woods Hole Oceanographic Institution), 2007.<br>Includes bibliographical references.<br>Surfzone wave height transformation and wave-breaking-driven increases in the mean sea level (setup) are examined on alongshore-uniform beaches with alongshore homogeneous and inhomogeneous wave forcing. While previously derived models predict wave heights adequately (root-mean-square errors typically less than 20%), the models can be improved by tuning a free parameter or by using a new parameterization based on the deep-water wave height. Based on a sensitivity analysis of the cross-shore momentum balance used to predict setup, a one-dimensional (1-D) model is developed that includes wave rollers and bottom stress owing to the mean offshore-directed flow. The model predicts setup accurately at three alongshore homogeneous field sites, as well as at a site where the incident wave field is alongshore non-uniform, suggesting that setup is driven primarily by the cross-shore (1-D) forcing. Furthermore, alongshore gradients of setup can be important to driving alongshore flows in the surfzone, and the 1-D setup model predicts these gradients accurately enough to simulate the observed flows.<br>by Alex Apotsos.<br>Ph.D.
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Yemm, Sean P. "Field Observation of setup." Thesis, Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 2004. http://library.nps.navy.mil/uhtbin/hyperion/04Jun%5FYemm.pdf.
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Thesis (M.S. in Meteorology and Physical Oceanography)--Naval Postgraduate School, June 2004.<br>Thesis advisor(s): Edward Thornton. Includes bibliographical references (p. 29-31). Also available online.
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D'Uva, Michael. "Motor Generator Dynamometer Setup." Thesis, D'Uva, Michael (2013) Motor Generator Dynamometer Setup. Other thesis, Murdoch University, 2013. https://researchrepository.murdoch.edu.au/id/eprint/21902/.
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The primary aim of this thesis was the further development and reconstruction of the Motor Generator Dynamometer set up. Once completed, the apparatus is to be used as a learning tool for the engineering students at Murdoch University, demonstrating key concepts of electric machines and their reactions to the change in load conditions. For the mention primary aim the design, construction and commissioning of a load bank had to be adapted to the initial setup to enable the students to alter the connected load. Measurements and control of the apparatus was achieved through National instruments NI 6014 data acquisition unit and National Instruments LabVIEW.
The understanding of the project and the work that had been previously completed was the first stage of the project. Understanding the current system setup including the:
• DAQ system
• AC motor
• DC Generator
The resolution of existing problems was attempted such as overcoming the interference induced by the variable Frequency drive, accurate speed measurement of the machines and calibration of the torque measurement. As the main priority associated with the development of this project was safety for undergraduate students to perform experiments without the risk of being injured. This is why a complete reconstruction of the set up must take place further information can be found in the guidelines and design approaches that have been developed.
Books on the topic "SETBP1"
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Philippines. Department of Science and Technology. Setup success. Dept. of Science and Technology, 2011.
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Knight, Tim, ed. High-Probability Trade Setups. John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9781119202431.
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Hazarika, Manjuri, and Uday Shanker Dixit. Setup Planning for Machining. Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-13320-1.
Full textBook chapters on the topic "SETBP1"
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Pütz, Ralph, and Ton Serné. "Vermessung des Setups Measurement of Setup." In Rennwagentechnik - Praxislehrgang Fahrdynamik. Springer Fachmedien Wiesbaden, 2017. http://dx.doi.org/10.1007/978-3-658-16102-6_1.
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Pütz, Ralph, and Ton Serné. "Vermessung des Setups Measurement of Setup." In Rennwagentechnik - Praxislehrgang Fahrdynamik. Springer Fachmedien Wiesbaden, 2019. http://dx.doi.org/10.1007/978-3-658-26704-9_1.
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Schlawin, Frank. "Interferometric Setups." In Springer Theses. Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-44397-3_5.
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Brogaard, Rasmus Y. "Experimental Setups." In Molecular Conformation and Organic Photochemistry. Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-29381-8_6.
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Becker, Jan. "Novel Setups." In Springer Theses. Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-31241-0_5.
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Wilson, Phil. "ASP.NET Setups." In The Definitive Guide to Windows Installer. Apress, 2004. http://dx.doi.org/10.1007/978-1-4302-0676-7_7.
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Jackman, John. "Interview Setups." In Lighting for Digital Video and Television. Routledge, 2020. http://dx.doi.org/10.4324/9781315676005-7.
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Mardan, Azat. "Setup." In Full Stack JavaScript. Apress, 2015. http://dx.doi.org/10.1007/978-1-4842-1751-1_2.
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Hagos, Ted. "Setup." In Android Studio IDE Quick Reference. Apress, 2019. http://dx.doi.org/10.1007/978-1-4842-4953-6_1.
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Baruah, Rakesh. "Setup." In Virtual Reality with VRTK4. Apress, 2019. http://dx.doi.org/10.1007/978-1-4842-5488-2_1.
Full textConference papers on the topic "SETBP1"
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Piazza, Rocco, Simona Valletta, Nils Winkelmann, et al. "Abstract 3176: Recurrent SETBP1 mutations in atypical chronic myeloid leukemia abrogate an ubiquitination site and dysregulate SETBP1 protein levels." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-3176.
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Redaelli, Sara, Simona Valletta, Rocco Piazza, et al. "Abstract 2993: Patterns of recurrent mutations in SETBP1 mutated and wild-type atypical Chronic Myeloid Leukemia patients." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-2993.
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Saito, Y., and K. Kobayashi. "Proposal of optical farming: development of several optical sensing instruments for agricultural use." In SPIE SeTBio, edited by Naoshi Kondo. SPIE, 2013. http://dx.doi.org/10.1117/12.2028830.
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Mat Nawi, Nazmi, Guangnan Chen, and Troy Jensen. "Application of visible and shortwave near infrared spectrometer to predict sugarcane quality from different sample forms." In SPIE SeTBio, edited by Naoshi Kondo. SPIE, 2013. http://dx.doi.org/10.1117/12.2029395.
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De Vylder, Jonas, Dominique Van Der Straeten, and Wilfried Philips. "Multiple leaf tracking using computer vision methods with shape constraints." In SPIE SeTBio, edited by Naoshi Kondo. SPIE, 2013. http://dx.doi.org/10.1117/12.2029789.
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Nguyen Do Trong, Nghia, Chyngyz Erkinbaev, Bart Nicolaï, Wouter Saeys, Mizuki Tsuta, and Josse De Baerdemaeker. "Spatially resolved spectroscopy for nondestructive quality measurements of Braeburn apples cultivated in sub-fertilization condition." In SPIE SeTBio, edited by Naoshi Kondo. SPIE, 2013. http://dx.doi.org/10.1117/12.2030407.
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Catalano, Pasquale, Flavio Fucci, Ferruccio Giametta, Giovanna La Fianza, and Biagio Bianchi. "Vibration analysis using a contactless acquisition system." In SPIE SeTBio, edited by Naoshi Kondo. SPIE, 2013. http://dx.doi.org/10.1117/12.2030414.
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Van Beers, Robbe, Ben Aernouts, Josse De Baerdemaeker, and Wouter Saeys. "Apple ripeness detection using hyperspectral laser scatter imaging." In SPIE SeTBio, edited by Naoshi Kondo. SPIE, 2013. http://dx.doi.org/10.1117/12.2030569.
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Kakinoki, Yoshiaki, Yuya Kato, Kosuke Ogawa, Akira Nakao, Zenshiro Okai, and Toshio Katsuyama. "Efficient plant growth using automatic position-feedback laser light irradiation." In SPIE SeTBio, edited by Naoshi Kondo. SPIE, 2013. http://dx.doi.org/10.1117/12.2030575.
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Sumriddetchkajorn, Sarun. "Mobile device-based optical instruments for agriculture." In SPIE SeTBio, edited by Naoshi Kondo. SPIE, 2013. http://dx.doi.org/10.1117/12.2030626.
Full textReports on the topic "SETBP1"
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Milbrath, Brian, and Aviva Joy Sussman. Lufkin_Exercise_ Setup. Office of Scientific and Technical Information (OSTI), 2017. http://dx.doi.org/10.2172/1392855.
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Jean, Brian Altom. LANL problem setup. Office of Scientific and Technical Information (OSTI), 2011. http://dx.doi.org/10.2172/1068931.
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Gillespie, L. K. Setup reduction approaches for machining. Office of Scientific and Technical Information (OSTI), 1997. http://dx.doi.org/10.2172/481589.
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Gardner, C. J. Booster Double Harmonic Setup Notes. Office of Scientific and Technical Information (OSTI), 2015. http://dx.doi.org/10.2172/1172091.
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