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Academic literature on the topic 'CREBBP'

Author: Grafiati

Published: 9 March 2023

Last updated: 10 March 2023

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Journal articles on the topic "CREBBP"

Meyer, Stefanie, Sofija Vlasevska, Laura Garcia Ibanez, Claudio Scuoppo, Riccardo Dalla-Favera, and Laura Pasqualucci. "Targeting Histone Acetyltransferase Gene Inactivation in Diffuse Large B Cell Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 671. http://dx.doi.org/10.1182/blood-2018-99-117542.

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Abstract Diffuse Large B-cell Lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, accounting for ~30% of de-novo diagnoses and also arising as a frequent clinical evolution of indolent lymphomas. Although curable in a substantial fraction of cases, one third of patients do not achieve durable remissions, highlighting the need for novel, targeted therapies. Over the past decade, we and others have identified the CREBBP acetyltransferase and, less frequently, its paralogue EP300 as highly recurrent targets of inactivating somatic mutations/deletions in DLBCL and follicular lymphoma (FL) (30% and 60% of patients, respectively), indicating a prominent role in the pathogenesis of these tumors (Pasqualucci et al., Nature 2011). In most cases, mutations are heterozygous and the residual wildtype (WT) allele is expressed, suggesting a haploinsufficient tumor suppressor role. Indeed, germinal center (GC)-specific loss of Crebbp perturbs the expression of genes that are relevant to the normal biology of this structure, i.e. the lymphoma cell of origin, and cooperates with BCL2 deregulation to increase the incidence of tumors recapitulating the features of the human disease (Zhang et al., Cancer Discovery 2017). Intringuingly, while CREBBP binds to virtually all GC-specific superenhancers, no detrimental effects were observed upon its deletion in mice, suggesting the existence of compensatory mechanisms. Consistent with this hypothesis, inactivation of CREBBP and EP300 rarely coexist in human DLBCL and FL, suggesting that cells require a certain amount of acetyltransferase activity. To investigate whether EP300 compensates for CREBBP loss in the GC, we analyzed the GC responses in compound mouse models engineered to specifically delete these two genes (alone and in combination) upon SRBC immunization and induction of a Cγ1-driven Cre-recombinase. While CrebbpKOmice showed a mild increase in GC formation, as reported, loss of Ep300 led to ~40% reduction in the percentage of GC cells (mean: 1.8% vs 3.1% in WT littermates; p<0.05), documenting that these two enzymes play non-entirely overlapping roles in this population. Importantly, GC formation was completely abrogated in CrebbpKOEp300KO mice and dramatically impaired in CrebbpHETEp300KO mice, as compared to both WT and single EP300KO mice. These data suggest that GC B cells require a minimum amount of acetyltransferase activity, and reveal a potential therapeutically exploitable dependency of Crebbp-mutated GC B cells on Ep300. In order to probe if a similar dependency exists in neoplastic GC B cells, we used an inducible CRISPR/Cas9 system to delete EP300 (or a control non-genic region) in 4 DLBCL cell lines representative of the various CREBBP genotypes found in DLBCL, and monitored cell proliferation and survival in competition assays over 12 days. Compared to CREBBPWT, CREBBP heterozygous and homozygous mutant cells were significantly counter-selected from the total population following doxycycline induced EP300 deletion (~30% at day 7). Moreover, no EP300-edited clones were recovered from the CREBBP mutant lines in single cell plating assays, compared to CREBBP WT (p<0.01). Thus, DLBCL cells remain addicted to the residual EP300 aceyltransferase activity, supporting the existence of a therapeutic window for EP300 inhibitors. To explore this concept further, we generated isogenic DLBCL clones carrying WT or defective CREBBP alleles (n=4 each), and performed drug-sensitivity assays with 2 novel small molecule inhibitors that specifically target the CREBBP/EP300 HAT or BRD domain. While, at higher doses, both inhibitors interfered with cell growth in all clones, CREBBPKO cells were significantly more sensitive than their isogenic WT pairsat low nanomolar ranges (IC50: 60nM vs 300nM). Importantly, we were able to design an in vitro protocol that was toxic to CREBBPKO cells but tolerated by CREBBPWT cells, providing a proof of concept for therapeutically targeting these molecules. In conclusion, we show that CREBBP and EP300 have differential roles in normal GC B cell development and that CREBBP mutated cells are addicted to the residual EP300 activity. This dependency is maintained in DLBCL cells, providing the basis for the potential application of acetyl transferase inhibition into the clinical settings. Disclosures No relevant conflicts of interest to declare.

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Ying, Hsia-Yuan, Yanwen Jiang, Ana Ortega-Molina, Huimin Geng, Dylan McNally, Ling Wang, Ashley Doane, et al. "Crebbp Mutations Disrupt Dynamic Enhancer Acetylation in B-Cells, Enabling HDAC3 to Drive Lymphomagenesis." Blood 128, no. 22 (December 2, 2016): 735. http://dx.doi.org/10.1182/blood.v128.22.735.735.

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Abstract Somatic mutations in CREBBP occur frequently in germinal center derived lymphomas such as DLBCL and FL. However whether or how these mutations might contribute to lymphomagenesis is still largely unknown. Most CREBBP mutations are predicted to result in loss of function since they target the histone acetyltransferase (HAT) domain or give rise to premature stop codon prior to the HAT domain. Here, we show that Crebbp shRNA knockdown (KD) accelerated lymphomagenesis in VavP-Bcl2 transgenic mice, a model that recapitulates human GC-derived lymphomas. The median time to lymphoma onset in VavP-Bcl2/CrebbpKD mice was 114 days, significantly shorter than control VavP-Bcl2/GFP mice (193 days, p=0.04). Histopathology revealed that VavP-Bcl2/CrebbpKD lymphomas were more aggressive and widely disseminated than VavP-Bcl2/GFP lymphomas. CREBBP can regulate gene enhancer function through H3K27 acetylation. ChIP-seq in VavP-Bcl2/CrebbpKD lymphoma cells revealed significant reduction of H3K27ac peaks compared to control lymphoma cells (N = 1717, Kolmogorov-Smirnov test, p<2.2E-16). Loss of H3K27ac was markedly skewed towards enhancers. We observed similar loss of enhancer H3K27ac in human DLBCL cells after CREBBP shRNA KD. Enhancer H3K27ac loss was significantly associated with repression of nearby genes in both murine (FDR q=0.044) and human lymphoma cells (FDR q=0). RNA-seq performed in three independent FL or DLBCL patient cohorts revealed a characteristic CREBBP mutant gene expression signature featuring prominent transcriptional repression (p=1.32E-14, p=0.001, and p=0.0002 respectively). Notably, the human patient CREBBP mutant signature was highly enriched in murine and human cell line CREBBP shRNA profiles (FDR=0, GSEA), indicating that CREBBP KD signature was highly similar to CREBBP mutant signature in humans. Functional analysis of the CREBBP mutant/KD signature showed significant enrichment of GC exit pathways including genes induced by CD40, IRF4 and plasma cell differentiation; as well as immune response processes including antigen processing and presentation, such as MHC class II genes (BH-adjusted p<0.05). To better understand mechanism we performed an integrative analysis of CREBBP signatures against databases of B-cell transcription factor and epigenome profiles. This analysis yielded significant enrichment (BH-adjusted p<0.05) for i) enhancers bound by the BCL6 transcriptional repressor and its SMRT/HDAC3 corepressor complex, ii) enhancers that are normally deacetylated in GC B-cells, and iii) genes induced by BCL6 siRNA. This is notable because in normal GCs BCL6 represses enhancers by recruiting SMRT/HDAC3 complexes to deacetylate H3K27. Hence our data suggest that CREBBP is a counteracting HAT to BCL6/SMRT/HDAC3. Indeed, conditional knockout of Hdac3 in GC B-cells in mice resulted in impaired GC formation and a transcriptional signature featuring upregulation of the same genes that are repressed by CREBBP KD (GSEA FDR=0). Moreover, CREBBP KD in DLBCL cells resulted in H3K27ac loss at BCL6/SMRT/HDAC3 regulated enhancers, including those nearby CDKN1A, NFATC1, FOXP1, and MHC II genes, such as HLA-DQA1 and HLA-DRB5. CREBBP KD also resulted in silencing of these genes. Since we show HDAC3 is the opposing HDAC to CREBBP then we reasoned that CREBBP mutant DLBCLs might be especially dependent on HDAC3. Indeed we observed that HDAC3 shRNA resulted in profound suppression of CREBBP mutant DLBCL cells in vitro and in vivo (DLBCL xenografts in mice, p=0.005), whereas CREBBP WT cell lines were barely affected by HDAC3 KD. The opposing effects of BCL6/SMRT/HDAC3 and CREBBP on MHC class II could have implications for immune surveillance. Accordingly CREBBP KD induced significant loss of cell surface HLA-DR molecules (p<0.05), and these cells exhibited up to 90% less capability to stimulate T-cell response in allogeneic mixed lymphocyte reaction experiments. The loss of MHC class II molecules and T-cell response was rescued when CREBBP loss of function cells were exposed to a specific HDAC3 inhibitor. In summary, CREBBP mutations drive lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, resulting in a repressive transcriptional programming that disrupts GC exit and evades immune surveillance. HDAC3 targeted therapy may rescue these effects and serve as a precision approach for CREBBP mutant lymphomas. Disclosures Scott: Celgene: Consultancy; Roche: Honoraria; Janssen: Consultancy; BC Cancer Agency: Patents & Royalties: Inventor on a patent licensed to NanoString Technologies. Tam:Millennium Pharmaceuticals, Inc.: Consultancy. Melnick:Janssen: Research Funding.

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Lamble, Adam J., Robert B. Gerbing, Jenny L. Smith, Rhonda E. Ries, Edward A. Kolb, Todd A. Alonzo, and Soheil Meshinchi. "Crebbp Alterations Are Associated with a Poor Prognosis in De Novo AML." Blood 138, Supplement 1 (November 5, 2021): 3451. http://dx.doi.org/10.1182/blood-2021-154052.

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Abstract Introduction: The translocation, t(8;16)(p11;p13), results in the fusion between KAT6A and CREBBP and has been associated with a poor prognosis in both pediatric and adult acute myeloid leukemia (AML). This lesion has therefore been re-classified as high risk on the active Phase 3 Children's Oncology Group (COG) trial for de novo AML, AAML1831 (NCT04293562). Less is known about the prognostic significance of CREBBP sequence variants. Methods: CREBBP variant status was determined in patients with AML enrolled on 4 successive COG trials for de novo pediatric AML (NCT00003790, NCT00070174, NCT01407757, NCT01371981). Fusions involving CREBBP were prospectively obtained via conventional cytogenetics and retrospectively confirmed via RNAseq. Insertions and deletions (indels) leading to frameshift mutations and single nucleotide variants (SNVs) were retrospectively interrogated via next generation sequencing. Results: Of 2216 patients (age: 0-29.8 years), 55 (2.5%) patients had an alteration involving CREBBP. Sixteen (29%) of these were a fusion involving CREBBP (CREBBP/fus), with KAT6A being the most common translocation partner (n=15) and the remaining translocation involving ANK1. The remaining 39 patients (71%) had a CREBBP mutation (CREBBP/mut), including 19 with an indel (CREBBP/indel) leading to a frameshift mutation and 20 with a SNV (CREBBP/SNV). We compared clinical and biologic characteristics between the three cohorts. CREBBP/fus patients were significantly younger than CREBBP/indel and CREBBP/SNV patients (median ages of 2.6 vs. 7.8 vs. 11.9 years; p=0.027). There was a higher prevalence of t(8;21)/RUNX1-RUNX1T1 in CREBBP/indel patients compared to CREBBP/SNV patients (42.1% vs. 5%; p=0.008). In contrast, CREBBP/SNV patients were more likely to be associated with a normal karyotype (40% vs. 5.3%; p=0.02). There was a similar prevalence of co-occurring high-risk lesions in CREBBP/indel (n=5; CBFA2T3-GLIS2, KMT2A-AFF1, KMT2A-MLLT4, MLLT10-PICALM, NUP98-HOXA9) and CREBBP/SNV (n=7; DEK-NUP214, ETV6-FOXO1, FUS-ERG, NUP98-NSD1, ETV6-MNX1, FLT3-ITDx2) patients. There was otherwise no difference between presenting WBC count, FLT3-ITD, NPM1, CEBPA, remission rates or MRD status after Induction 1 therapy. Patients with any CREBBP alteration had a significantly worse 5-year event free survival (EFS) compared to patients without (25.9% vs. 45.2%; p=0.002) and this inferior EFS overlaps with contemporarily defined high-risk patients (Figure 1a). Evaluation of outcomes based on type of alteration demonstrated a similar 5-year EFS of 33.3% and 23.1% between CREBBP/fus and CREBBP/mut patients, respectively (Figure 1b; p=0.832). This poor EFS was maintained in the CREBBP/indel patients with a co-occurring t(8;21) (n=8, 5-year EFS 12.5%). When patients with co-occurring high-risk lesions were excluded from analysis, the remaining CREBBP/mut (n=27) patients maintained their poor EFS (29.6%). Despite their poor EFS, CREBBP/mut patients had an analogous overall survival (OS) to non-CREBBP patients (57.4% vs. 62.3%; p=0.499, Figure 1c), demonstrating that these patients could be successfully salvaged following relapse. In contrast, all patients with CREBBP/fus that relapsed subsequently died from their disease (OS 33.3%). Conclusions: In a large study of CREBBP alterations in pediatric patients with de novo AML, we show that these patients have a dismal EFS, regardless of alteration type. Further, despite enrichment of t(8;21), the favorable prognosis typically conferred by this alteration was abrogated by the co-occurrence of CREBBP/indel. Similarly, by excluding patients with co-occurring high-risk lesions from analysis, we show that these poor outcomes persist in a cohort of patients that would otherwise be considered low risk. Translocations between CREBBP and KAT6A in patients over 90 days of age are considered high risk on the active COG phase 3 trial. Given the inferior EFS and high salvage rates associated with other CREBBP alterations, intensification of upfront treatment, including hematopoietic stem cell transplant, should be considered in this population. The authors would like to acknowledge Astellas Pharma Global Development, Inc. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Zhu, Yu, Zi Wang, Yanan Li, Hongling Peng, Jing Liu, Ji Zhang, and Xiaojuan Xiao. "The Role of CREBBP/EP300 and Its Therapeutic Implications in Hematological Malignancies." Cancers 15, no. 4 (February 14, 2023): 1219. http://dx.doi.org/10.3390/cancers15041219.

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Disordered histone acetylation has emerged as a key mechanism in promoting hematological malignancies. CREB-binding protein (CREBBP) and E1A-binding protein P300 (EP300) are two key acetyltransferases and transcriptional cofactors that regulate gene expression by regulating the acetylation levels of histone proteins and non-histone proteins. CREBBP/EP300 dysregulation and CREBBP/EP300-containing complexes are critical for the initiation, progression, and chemoresistance of hematological malignancies. CREBBP/EP300 also participate in tumor immune responses by regulating the differentiation and function of multiple immune cells. Currently, CREBBP/EP300 are attractive targets for drug development and are increasingly used as favorable tools in preclinical studies of hematological malignancies. In this review, we summarize the role of CREBBP/EP300 in normal hematopoiesis and highlight the pathogenic mechanisms of CREBBP/EP300 in hematological malignancies. Moreover, the research basis and potential future therapeutic implications of related inhibitors were also discussed from several aspects. This review represents an in-depth insight into the physiological and pathological significance of CREBBP/EP300 in hematology.

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Hashwah, Hind, Corina A. Schmid, Sabrina Kasser, Katrin Bertram, Anna Stelling, Markus G. Manz, and Anne Müller. "Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth." Proceedings of the National Academy of Sciences 114, no. 36 (August 22, 2017): 9701–6. http://dx.doi.org/10.1073/pnas.1619555114.

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The genes encoding the histone acetyl-transferases (HATs) CREB binding protein (CREBBP) and EP300 are recurrently mutated in the activated B cell-like and germinal center (GC) B cell-like subtypes of diffuse large B cell lymphoma (DLBCL). Here, we introduced a patient mutation into a human DLBCL cell line using CRISPR and deleted Crebbp and Ep300 in the GC B cell compartment of mice. CREBBP-mutant DLBCL clones exhibited reduced histone H3 acetylation, expressed significantly less MHCII, and grew faster than wild-type clones in s.c. and orthotopic xenograft models. Mice lacking Crebbp in GC B cells exhibited hyperproliferation of their GC compartment upon immunization, had reduced MHCII surface expression on GC cells, and developed accelerated MYC-driven lymphomas. Ep300 inactivation reproduced some, but not all, consequences of Crebbp inactivation. MHCII deficiency phenocopied the effects of CREBBP loss in spontaneous and serial transplantation models of MYC-driven lymphomagenesis, supporting the idea that the mutational inactivation of CREBBP promotes immune evasion. Indeed, the depletion of CD4+ T cells greatly facilitated the engraftment of lymphoma cells in serial transplantation models. In summary, we provide evidence that both HATs are bona fide tumor suppressors that control MHCII expression and promote tumor immune control; mutational inactivation of CREBBP, but not of EP300, has additional cell-intrinsic engraftment and growth-promoting effects.

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Zimmer, Stephanie N., Qing Zhou, Ting Zhou, Ziming Cheng, Sherry L. Abboud-Werner, Diane Horn, Mike Lecocke, et al. "Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis." Blood 118, no. 1 (July 7, 2011): 69–79. http://dx.doi.org/10.1182/blood-2010-09-307942.

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Abstract CREB-binding protein (CREBBP) is important for the cell-autonomous regulation of hematopoiesis, including the stem cell compartment. In the present study, we show that CREBBP plays an equally pivotal role in microenvironment-mediated regulation of hematopoiesis. We found that the BM microenvironment of Crebbp+/− mice was unable to properly maintain the immature stem cell and progenitor cell pools. Instead, it stimulates myeloid differentiation, which progresses into a myeloproliferation phenotype. Alterations in the BM microenvironment resulting from haploinsufficiency of Crebbp included a marked decrease in trabecular bone that was predominantly caused by increased osteoclastogenesis. Although CFU-fibroblast (CFU-F) and total osteoblast numbers were decreased, the bone formation rate was similar to that found in wild-type mice. At the molecular level, we found that the known hematopoietic modulators matrix metallopeptidase-9 (MMP9) and kit ligand (KITL) were decreased with heterozygous levels of Crebbp. Lastly, potentially important regulatory proteins, endothelial cell adhesion molecule 1 (ESAM1) and cadherin 5 (CDH5), were increased on Crebbp+/− endothelial cells. Our findings reveal that a full dose of Crebbp is essential in the BM microenvironment to maintain proper hematopoiesis and to prevent excessive myeloproliferation.

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Huntly, Brian J. P., Sarah Jayne Horton, George Giotopoulos, Haiyang Yun, Shabana Vohra, Olivia Sheppard, Rachael Bashford-Rogers, et al. "Early Loss of CREBBP Confers Malignant Stem Cell Properties on Lymphoid Progenitors." Blood 128, no. 22 (December 2, 2016): 460. http://dx.doi.org/10.1182/blood.v128.22.460.460.

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Abstract Loss-of-function mutations of the cyclic-AMP response element binding protein, binding protein (CREBBP) gene have recently been described at high frequencies across a spectrum of lymphoid malignancies, particularly follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The multiple effects of this epigenetic regulator on developmental and homeostatic processes have been extensively studied, however, exactly how CREBBP functions as a tumor suppressor and the reasons for its particular predilection for suppression of lymphoid tumors remains unclear. In addition, for many mature lymphoid malignancies, the existence of cancer stem cells is unproven and their provenance and the initial target cell for transformation a source of ongoing debate. Here we use multiple mouse strains to model loss of Crebbp in different lymphoid compartments to address these questions. We demonstrate that early loss of Crebbp in hematopoietic stem and progenitor cells (HSPC), through disruption by the Mx1-Cre recombinase, leads to increased development of hematological malignancies, particularly of the B-lymphoid lineage that mimic features of human lymphomas. Theses B-cell malignancies are of long latency and are preceded by significant alterations in the proliferation, self-renewal and differentiation of lymphoid progenitors, allowing hyperproliferative lymphoid progenitors whose differentiation is blocked to accumulate. Using an aberrant surface phenotype that resembles the eventual tumor, we identify a pre-malignant population in the peripheral blood of animals that is often evident many months before any disease characteristics. We demonstrate pre-malignant stem cell characteristics for this population in functional experiments, where it generates high level reconstitution of peripheral blood in transplant recipients, but only gives rise to disease in these animals after a long latency. We also utilize this unique cellular population in longitudinal genome scale analyses (clonality, RNA-Seq, ChIP-Seq and exome sequencing) to document the mechanisms of malignant evolution. Linking the increased rate of mutation we describe to Crebbp loss, we also demonstrate increased DNA damage and an altered DNA-damage response in premalignant lymphoid progenitors. Importantly, using a Cd19-Cre recombinase that excises only within committed lymphoid cells, we are able to demonstrate that when Crebbp is lost at a later stage of lymphoid development, the marked cellular abnormalities described above are completely lost and the development of tumors is no different from normal (Figure, below). Taken together, these findings define the developmental stage-specific tumor suppressor functions of Crebbp and shed light on the cellular origins and subsequent evolution of lymphoid malignancies. In addition, the altered response to DNA damage that we demonstrate upon loss of Crebbp, allied to the increased exposure to physiological DNA-damage during lymphoid ontogeny offers an explanation for the high incidence of CREBBP mutations in mature lymphoid malignancies. Figure Left panel, Kaplan Meier graph for Mx1-Cre Crebbp mice with loss of Crebbp in the HSPC compartment demonstrates significantly shorter survival vs WT littermates with intact expression of Crebbp. In contrast, when Crebbp is excised in a later lymphoid compartment through Cd19-Cre mediated recombination, right panel, no difference in survival is noted from WT littermate controls. Figure. Left panel, Kaplan Meier graph for Mx1-Cre Crebbp mice with loss of Crebbp in the HSPC compartment demonstrates significantly shorter survival vs WT littermates with intact expression of Crebbp. In contrast, when Crebbp is excised in a later lymphoid compartment through Cd19-Cre mediated recombination, right panel, no difference in survival is noted from WT littermate controls. Disclosures Huntly: Novartis: Speakers Bureau; BMS: Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Speakers Bureau.

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Idoia, García-Ramírez, Shashank Shrishrimal, Ines Gonzalez-Herrero, Alberto Martín-Lorenzo, Guillermo rodriguez-Hernandez, Romain Duval, Dalia Moore, et al. "CREBBP Loss Cooperates with BCL2 Over-Expression to Promote Lymphoma in Mice." Blood 128, no. 22 (December 2, 2016): 458. http://dx.doi.org/10.1182/blood.v128.22.458.458.

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Abstract Follicular lymphoma (FL) is genetically characterized by translocations of the BCL2 oncogene that are found in ~90% of patients, and mutations of chromatin modifying genes that are found in up to 96% of patients. The latter include inactivating mutations of KMT2D and CREBBP, and activating mutations of EZH2, among others. However, CREBBP has yet to be investigated using this approach. We recently defined the evolutionary hierarchy of somatic mutations in FL and found that CREBBP mutations were most frequently acquired as early events during disease evolution and were maintained throughout disease progression and transformation. Recent studies, using transgenic mouse models, have shown that inactivation of KMT2D and introduction of the activating EZH2 mutation results in perturbed B-cell development and lymphomagenesis. Here, we extended upon these observations by performing targeted next generation sequencing of an additional cohort of tumors allowing the identification of the spectrum of CREBBP mutations across 200 FLs. This identified CREBBP mutations in 55% of tumors, and found that 31% of these mutations reside within the lysine acetyltransferase domain. Furthermore, 30% of mutations altered a single amino acid, arginine 1408, to either a cysteine or histidine residue. We performed a sensitive in vitro acetyltransferase assay for these point mutants and show that they result in >90% loss of catalytic activity. As our results show that CREBBP mutations result in a loss of function, we modeled these events in mice by floxing one or both alleles of Crebbp and crossing with the Mb1-cre strain. This yielded mice that deleted Crebbp specifically in B-cells. We additionally crossed these mice with the EµBcl2 strain that over-expresses Bcl2 in B-cells. Inactivation of Crebbp in B-cells was associated with deficits in B-cell development, with significantly reduced numbers of total B-cells that were contributed to by reductions in multiple B-cell subsets. These deficits were partially rescued by the EµBcl2 transgene. After 14-21 months, some mice became ill and necropsy revealed lymphadenopathy and splenomegaly as a result of B-cell lymphoma. We noted increased penetrance and decreased latency of lymphoma with one vs two alleles of Crebbp deleted, and with absence vs presence of the EµBcl2 transgene (Figure 1). We investigated the molecular etiology of these tumors by isolating splenic B-cells from these mice and performing transcriptome profiling and epigenetic profiling for the histone H3 lysine 18 acetylation (H3K18Ac) mark that is catalyzed by Crebbp. Transcriptional profiling identified a signature of 335 genes with increased expression and 370 genes with decreased expression, including an incremental increase in Myc expression when one or both alleles of Crebbp were deleted, respectively. Surprisingly, changes in transcript abundance were not associated with changes in H3K18Ac in the proximal regulatory regions of those genes. Regions of significantly altered H3K18Ac were instead localized primarily to intragenic regions. Analysis of the DNA sequences in these regions identified a significant enrichment of motifs that contained Myc consensus sequences, and these were present in >60% of regions with altered H3K18Ac. In addition, ChIP-seq data from the ENCODE database showed a strong level of Myc binding to the center of these regions with altered H3K18Ac. Together, our results demonstrate that inactivating mutations of Crebbp may have a role in altering B-cell development. The significant induction of Myc expression that was associated with Crebbp deletion, and epigenetic changes in regions that are bound by Myc, suggest that Crebbp inactivation may have a role in the induction of Myc expression and activity. This may be important with respect to transformation of FL, which may proceed via induction of MYC. However, our results also demonstrate some important discrepancies between the role of CREBBP mutations in human FL, and the role of Crebbp deletion in murine models. Disclosures Lunning: Celgene: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Juno: Consultancy; Bristol-Myer-Squibb: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy.

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Dixon, Zach, Julie A. E. Irving, and Lindsay Nicholson. "Crebbp K nockdown Does Not Impact on Glucocorticoid Induced Apoptosis in Childhood Acute Lymphoblastic Leukemia." Blood 126, no. 23 (December 3, 2015): 1429. http://dx.doi.org/10.1182/blood.v126.23.1429.1429.

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Abstract Childhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer and, despite a cure rate approaching 90%, relapse is a significant cause of death in young people. Recently it has been shown that inactivating mutations in the histone acetyltransferase, CREB binding protein (CREBBP or CBP) are frequently seen at relapse in childhood ALL, with enrichment in high hyperdiploid and hypodiploid cases. Mutations are usually heterozygous, suggesting haploinsufficiency, and are often acquired at relapse, implying a role in drug resistance. Since glucocorticoid (GC) response genes are known targets of CREBBP and, given the pivotal role of GCs in ALL therapy, it has been postulated that CREBBP mutations confer GC chemoresistance. CREBBP is a multifunctional protein, playing a role in cAMP dependent signalling, acetylation mediated activation of p53 and inactivation of BCL6 and a range of DNA damage repair pathways including base excision repair (BER) and direct DNA damage repair. To assess the role of CREBBP haploinsufficiency in ALL, RNAi techniques were used to create isogenic CREBBP knockdown models of ALL. CREBBP knockdown was carried out using small hairpin RNA (shRNA) transduction (termed shCBP cells) or small interfering RNA (siRNA) transfection (termed siCBP cells) in the PreB 697 B-cell precursor cell line (t(1;19)) and the hypodiploid MHH-CALL-2 cell line, as well as high hyperdiploid primagraft ALL cells. Knockdown of at least 50% of control was confirmed at both mRNA and protein level. The functional impact of CREBBP knockdown in cells was determined by analysis of known CREBBP target residues; acetyl H3K18 and H3K27, and transcription of cAMP dependent genes (CXCR4, MKNK2, DUSP5, DUSP10 and RGS16). To assess the impact of CREBBP knockdown on response to GCs, cells were treated with dexamethasone and expression of the classic glucocorticoid receptor (GR) targets; GILZ and FKBP51, was assessed by quantitative reverse transcriptase PCR (QRT-PCR). Alamar blue cell viability assays were used to determine the sensitivity of each CREBBPknockdown model to dexamethasone compared to isogenic controls. Three out of four cell models displayed a reduction in H3K18 or H3K27 acetylation compared to isogenic control, indicating a relevant functional impact of CREBBP knockdown. Cell lines showed a trend towards reduced induction of some of the selected cAMP dependent targets but statistical significance was not achieved (p values >0.2). Gene expression profiling and Ingenuity Pathway Analysis of PreB 697 shCBP cells compared to isogenic control predicted that upstream transcription of NR3C1, the gene encoding the GR, would be affected in CREBBP knockdown cells. However, while induction of GILZ and FKBP51 in PreB 697 shCBP cells in response to GC was significantly impaired in knockdown compared to control cells (GILZ p=0.009, FKBP51 p=0.03), they were no more resistant to dexamethasone (p=0.9). This was mirrored in siCBP cell lines and primagraft cells, where a significant impairment in basal expression of GILZ and/or FKBP51 was seen in some lines (GILZ reduction; p=0.03 PreB 697 shCBP, p=0.02 PreB 697 siCBP, FKBP51 reduction; p=0.01 primagraft siCBP cells) but no significant impairment in the transcriptional induction of these genes in response to GC compared to isogenic control was observed (p values >0.5). Importantly, no decreased sensitivity to dexamethasone was seen in any model after CREBBP knockdown (p values >0.1). CREBBP knockdown in ALL cells had no significant effect on the induction of cAMP dependent genes, had a variable effect on GR target expression, but consistently showed no impact on GC sensitivity, regardless of cytogenetic context. These data show that the acquisition of CREBBP mutations at relapse in childhood ALL is not mediated through GC resistance and suggest that other CREBBP associated mechanisms, such as DNA damage repair, may influence drug response. Understanding the role of CREBBP in carcinogenesis and drug resistance is crucial as it is implicated as a tumour suppressor in a growing number of cancers, making it a potential multi-tumour target for novel therapies. Disclosures No relevant conflicts of interest to declare.

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Xu, Abai, and Tingting Chen. "Abstract 5102: Correlation analysis of CREBBP mutation with tumor mutation burden and effect of immune checkpoint therapy in bladder cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5102. http://dx.doi.org/10.1158/1538-7445.am2022-5102.

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Abstract Background: CREB-binding protein (CREBBP, hereafter CBP) encoded the protein having intrinsic histone acetyltransferase activity, which stabilized the additional protein interactions with the transcription complex. The mutation of CREBBP has been reported that caused Rubinstein-Taybi syndrome (RTS) and associated with acute myeloid leukemia, but not been studied in bladder cancer (BLCA). Immune checkpoint therapy (ICI) has significantly became one of the primary treatment of BLCA, and Tumor mutation burden (TMB) has been regarded as the most prevalent biomarker to predict immunotherapy. The CREBBP mutation status correlation with TMB and immune response remain unknown. Methods: Whole exome sequencing (WES) data and clinical data of 406 BLCA patients was obtained from the Cancer Genome Altas (TCGA). The mutation data of 206 FFPE tumor samples from Chinese BLCA patients were sequenced by targeted next-generation sequencing (NGS, 3DMed panel). NGS data and clinical data of 192 advanced BLCA patients treated with ICI were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC). The association between CREBBP mutation and TMB level in BLCA were explored. Survival analysis was determined by Kaplan-Meier (KM) analysis. Results: In total, The CREBBP mutation frequency was 16.25% (66/406) of BLCA patients in TCGA, 14.56% (30/206) in Chinese cohort and 13.54 (26/192). In Chinese cohort, the alteration frequency of NOTCH signal pathways affected was 48.54% (100/206), in which the highest frequency genes was CREBBP. The TMB level in CREBBP mutant group was higher than wild-type group both in Chinese group (Wilcoxon test, p = 0.001) and MSKCC cohort (Wilcoxon test, p < 0.001). The survival analysis were performed on patients from TCGA cohorts without treatment information and MSKCC BLCA patients treated with ICIs, separately. In TCGA cohort, there are not significantly difference between CREBBP mutation group (n=65) and wild-type group (n=340). While in MSKCC ICIs treatment cohort, the overall survival (OS) of CREBBP mutation group (n=26) were significantly longer than wild-type group (n=166) (median OS, mutation vs wild-type = NE vs 15 months; HR 0.468 [95% CI 0.26-0.84]; P = 0.0431). Conclusion: The CREBBP gene mutation was associated with higher TMB level. Clinical cohort analysis results suggested that CREBBP might be a predictive biomarker of immune checkpoint therapy but not a prognostic factor in BLCA. Citation Format: Abai Xu, Tingting Chen. Correlation analysis of CREBBP mutation with tumor mutation burden and effect of immune checkpoint therapy in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5102.

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Dissertations / Theses on the topic "CREBBP"

Dixon, Zach Adam. "The role of CREBBP mutations in lymphoid malignancies." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3556.

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Relapsed acute lymphoblastic leukaemia (ALL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) comprise a group of malignancies with poor prognosis and therapeutic strategies are needed to improve outcomes. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP, are frequent in these malignancies, and are thought to lead to impaired transcription of glucocorticoid (GC) response genes. Given the pivotal role of GC in the treatment of lymphoid malignancies and the finding that CREBBP mutations often arise at relapse, it has been postulated that CREBBP mutations confer chemoresistance to GC therapy. To study the role of CREBBP haploinsufficiency in ALL, DLBCL and FL, small hairpin RNA and small interfering RNA methods were used to knock down CREBBP in a number of cell lines and primary derived samples. Models were functionally relevant, with reduced acetylation of CREBBP target residue, histone 3 lysine 18 and/or histone 3 lysine 27, but knockdown had no significant impact on activation of cAMP-dependent target genes. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models of ALL, and there was no significant difference in GC-induced apoptosis or chemosensitivity to other therapeutic agents frequently used in lymphoid malignancies, including histone deacetylase inhibitors. However, CREBBP knockdown was associated with enhanced signalling of the RAS/RAF/MEK/ERK pathway in RAS pathway mutant ALL cells, and MEK inhibitor sensitivity was retained. This suggests that CREBBP mutation may act to enhance the activity of oncogenes and that CREBBP/RAS pathway mutated relapsed ALL are candidates for MEK inhibitor clinical trials.

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Dawes, Joanna Camilla. "Modelling Crebbp loss in BCL2 driven non-Hodgkin's lymphoma." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/58194.

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Non-Hodgkin’s lymphomas (NHL) are a spectrum of hematopoietic cancer accounting for 4% of new cancer diagnoses each year. Approximately 95% of all NHL are of B-cell origin; diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma (FL) accounting for 30-40% and 20% of B-NHL respectively. Recent human mutation profiling and resequencing studies have shown that CREBBP and BCL2 are frequently mutated, early events in B-NHL that are often are concurrent. This thesis presents a study of their role in oncogenesis by generating a novel model of B-NHL overexpressing BCL2 in the haematopoetic compartment combined with the conditional heterozygous loss of Crebbp in the germinal centre B-cells. Loss of Crebbp significantly accelerated BCL2 driven lymphomagenesis. Characterisation of these lymphomas by flow cytometry demonstrated that they were phenotypically similar to mature human B-cell lymphomas of germinal centre origin. Additionally an insertional mutagenesis screen was performed in mice sensitised to B-NHL. Somatic MoMuLV caused mutations interact with the sensitising mutations, facilitating tumourigenesis and recapitulating the stepwise and accumulative progression of human disease. Provirus insertions were detected using a novel method of insertion site cloning called UMI-LM-PCR which amplifies the region flanking the provirus. Insertions were then mapped to the mouse genome flagging genes with a putative role in tumourigenesis. This method represents the highest throughput method to date and its applicability to Illumina sequencing permits the most comprehensive quantitative survey of subclonal mutations. This work confirms Crebbp is a tumour suppressor gene and that its loss cooperates with overexpression of BCL2 to accelerate lymphomagenesis. Through insertional mutagenesis screening of this model hundreds of putative cancer genes have been identified including Pou2f2 and Tfrc which have a propensity for mutation specifically in B-cell lymphomas deficient in Crebbp and overexpressing BCL2. These candidates now need to be validated to better characterise their role in B-cell lymphoma.

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BENTIVEGNA, ANGELA. "Ricerca di alterazioni del Gene CREBBP (CREB Binding Protein) in pazienti con sindrome di Rubinstein-Taybi." Bachelor's thesis, Università degli Studi di Milano-Bicocca, 2004. http://hdl.handle.net/10281/12824.

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Di, Dio Laura Giusy Rosaria Agata. "Sindrome da microduplicazione 16p13.3 espansione del fenotipo." Doctoral thesis, Università di Catania, 2012. http://hdl.handle.net/10761/1062.

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Le sindromi da microalterazione cromosomica sono sindromi costituzionali con ritardo mentale e anomalie fenotipiche multiple causate da sbilanci di specifiche regioni del genoma. Se il riarrangiamento cromosomico include poche megabasi viene detto criptico perché spesso non è diagnosticabile con un esame cromosomico convenzionale. Per molti anni, tuttavia, cioè fino a quando è stata disponibile solo la tecnica tradizionale e FISH per l analisi di cromosomi metafasici, erano conosciute soltanto le microdelezioni delle regioni fiancheggiate da dupliconi. La mancata diagnosi citogenetica-molecolare delle microduplicazioni è stata attribuita a vari possibili fattori: ad un evento selettivo di microdelezione mediato dai dupliconi, ad una mancata penetranza clinica della duplicazione, che, essendo in genere meglio tollerata sul piano fenotipico rispetto alla delezione, può sfuggire all accertamento clinico. In realtà l applicazione della tecnica array-CGH nella diagnosi del ritardo mentale idiopatico, sta dimostrando come le stesse regioni interessate da microdelezione siano spesso interessate da microduplicazione, con possibile fenotipo clinico, confermando che il meccanismo di ricombinazione omologa non allelica è un frequente e specifico meccanismo di mutazione cromosomica strutturale. Nel genoma sono presenti CNV (copy number variation) o polimorfismi (delezioni, duplicazioni, amplificazioni) che hanno diverse dimensioni da 40kb a 2Mb e sono ampiamente distribuiti in tutto il genoma. Vista l ampia distribuzione di CNV lo studio del DNA parentale aiuta l interpretazione dei dati forniti dagli array-CGH. Un ulteriore tipologia della tecnica di array-CGH è quella definita SNP array (Single Nucleotide Polymorphism). Questa metodologia sfrutta l elevato polimorfismo di genomi individuali relativi a singoli nucleotidi. La tecnica SNP array è in grado di diagnosticare non solo variazioni quantitative del genoma ma anche le disomie uniparentali, l origine parentale di uno sbilancio. Riportiamo un caso con caratteristiche fenotipiche riconoscibili, ritardo psicomotorio e di crescita, in cui è stata rilevata dagli SNP-array una duplicazione di 0.4 Mb nella regione cromosomica 16p13.3. Tale regione è implicata nella sindrome di Rubinstein Taybi, dovuta a microdelezione della regione o delezione del gene CREBBP o mutazione del gene CREBBP con loss of function.

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BENTIVEGNA, ANGELA. "Base molecolare della sindrome di Chromatin remodelling Rubinstein-Taybi: un sistema modello per lo studio dei deficit funzionali di acetilazione istonica." Doctoral thesis, Università degli studi di Milano, 2008. http://hdl.handle.net/10281/12823.

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Rubinstein–Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 63 Italian RSTS patients (pts), 6 deletions were identified, 3 of which were in a mosaic condition that has not been previously reported in RSTS. The clinical presentation was typical in all cases, but more severe in the three pts carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS. The use of region-specific BAC clones and small CREBBP probes allowed to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5–10 kb. Four of five intragenic breakpoints cluster at the 5' end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS pts and tumours. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. Searching for mutations of CREBBP gene in 56 patients revealed 23 different mutations. In addition, one deletion and two amplifications were identified by a-CGH in 20 RSTS pts.

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Camós, Guijosa Mireia. "Caracterización biológica de la leucemia mieloide aguda con translocación t(8;16)(p11;p13) y reordenamiento MYST3-CREBBP." Doctoral thesis, Universitat de Barcelona, 2007. http://hdl.handle.net/10803/2220.

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INTRODUCCIÓN. La leucemia mieloide aguda (LMA) es una enfermedad heterogénea desde el punto de vista clínico y biológico. En los últimos años se vienen reconociendo diversas alteraciones moleculares que definen entidades específicas. En este contexto, la LMA con translocación t(8;16)(p11;p13) y reordenamiento MYST3 (MOZ)/CREBBP (CBP) es una variedad infrecuente mal caracterizada desde el punto de vista biológico.

HIPÓTESIS Y OBJETIVOS. La proteína quimérica MYST3-CREBBP, resultante de la translocación t(8;16)(p11;p13), podría conferir a este subtipo de LMA una individualidad biológica propia, con rasgos diferenciados respecto al resto de leucemias. Para confirmar esta hipótesis general los objetivos de la presente tesis doctoral fueron: 1) diseñar una técnica de PCR para el diagnóstico rápido y específico del reordenamiento MYST3-CREBBP; 2) caracterizar el punto de ruptura de los genes implicados en la translocación en una serie de pacientes y 3) estudiar el perfil de expresión génica de las LMA con reordenamiento MYST3-CREBBP y compararlo con el de otros subtipos bien definidos de LMA.

PACIENTES Y MÉTODOS. Se estudió una serie de pacientes con LMA y reordenamiento MYST3-CREBBP (n=7) y se compararon sus características biológicas con otros casos de LMA. Para ello se diseñó una técnica de PCR nueva para la detección del reordenamiento MYST3-CREBBP, mientras que los puntos de ruptura de los genes implicados en la translocación se estudiaron mediante secuenciación directa. El estudio del perfil de expresión génica de la LMA con reordenamiento MYST3-CREBBP se abordó utilizando microarrays de oligonucleótidos (Affymetrix HU133A). La diferencia entre la expresión génica entre diferentes subtipos de leucemia se analizó con diversas técnicas estadísticas (ANOVA, t-test), utilizando diferentes programas informáticos. Los resultados de este análisis se validaron en una serie independiente de pacientes estudiados mediante RT-PCR cuantitativa utilizando arrays de baja densidad.

RESULTADOS. Los pacientes afectos de LMA con reordenamiento MYST3-CREBBP presentaron un inmunofenotipo característico (CD34-, HLA-DR-, CD117-, CD56+, expresión de marcadores mielomonocíticos). Por otro lado, el análisis molecular reveló que el tránscrito tipo I del gen quimérico MYST3-CREBBP es el más común en estos pacientes. Por otra parte, el análisis sobre el perfil de expresión génica mostró una firma característica para las LMA con reordenamiento MYST3-CREBBP, consistente en la sobreexpresión de determinados genes HOX (HOXA9, HOXA10), de los oncogenes RET y PRL y la infraexpresión de genes como CCND2, STAT5 y WT1. Por otro lado, se observó una similitud en la expresión de algunos genes entre las leucemias MYST3-CREBBP y las LMA con reordenamiento de MLL, lo que sugiere un mecanismo de leucemogénesis parcialmente compartido por los dos tipos de leucemia.

CONCLUSIONES. La técnica de RT-PCR implementada es útil para la detección rápida del reordenamiento MYST3-CREBBP. El denominado tránscrito tipo I del gen quimérico MYST3-CREBBP es el más común en la LMA con t(8;16). La LMA con reordenamiento MYST3-CREBBP posee un perfil de expresión característico, con sobreexpresión de diversos oncogenes como RET y PRL y la presencia de un patrón específico de expresión de los genes homeobox.

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Torres, Leuridan Cavalcante. "Avaliação da imunocompetência de portadores da síndrome de Rubinstein-taybi." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-01092008-192345/.

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A síndrome de Rubinstein-Taybi (RTS, OMIM 180849) é uma doença autossômica dominante caracterizada por dismorfismos craniofaciais típicos, polegares e háluces alargados, infecções respiratórias recidivantes, retardo mental e de crescimento. RTS está associada com mutação no gene CREBBP. Na avaliação da imunocompetência de 17 portadores de RTS, observaram-se algumas alterações na resposta imune inata e adaptativa: leucocitose persistente, neutrófilos com desgranulopoiese, elevada concentração sérica de IgM e IgG1, produção normal de anticorpos contra antígenos protéicos e anti-polissacarídeos, elevados valores absolutos de células B totais, B \"naive\", B de memória, subpopulação B1 e de linfócitos B com IgM de membrana, e elevado percentual de apoptose de linfócitos B. DTH negativo para três antígenos e baixa resposta linfoproliferativa para antígenos protéicos. Diante do exposto, concluímos que os pacientes RTS apresentam alterações em vários mecanismos da resposta imune e principalmente, na imunidade humoral. Portanto, com este trabalho foi possível identificar as principais alterações imunológicas destes pacientes, e com isso, caracterizar quais os defeitos da resposta imune que pode estar associada com gene CREBBP.
Rubinstein-Taybi syndrome (RTS, OMIM 180849) is a dominant Mendelian disorder characterized by craniofacial dysmorphisms, broad thumbs and toes, mental retardation and growth and recurrent respiratory infections. RTS is classically associated with CREBBP gene mutations, but recently, p300 gene mutations were reported in three individuals. In imunonocompetence investigation of a group of 17 patient of the RTS, we found that the patients really show alterations in more than one arm of the immune response. The main alterations were found in: a) innate immunity, patients have defects in the distribution of the granules citoplasmatic and partial absence of F-actin filament part of its polymorphonuclear cells. In addition, some patients had decreased phagocytic activity, b) humoral immunity: elevated serum IgM antibodies and IgG1 subclass, normal production of antibodies for protein antigens and antipolysaccharide, high absolute values of B cell total, B \"naive\", B memory, subpopulation B1 and B lymphocytes with the membrane IgM, and high percentage of apoptosis of B lymphocytes; c) cellular immunity: delayed hypersensitivity skin tests negative for three antigens and low lymphoproliferative response to protein antigens. Values reduced percentage of CD45RA+ , CD45RO+ T cells and high doublepositive CD45RA+/CD45RO +) T cell. Ahead of the severe recurrent respiratory infections that affect the patients with RTS, and of the evaluation of immunocompetence of these patients, we find that they have several alterations in mechanisms of immune response and mainly in humoral immunity. Therefore, with this study was to identify the major immunological alterations of these patients, and with this, which characterize the main defects of the immune response of the patients RTS that can is associated with gene CREBBP.

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Djavanroodi, Faramarz. "Creep and creep-fracture crack growth." Thesis, Imperial College London, 1989. http://hdl.handle.net/10044/1/47412.

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Whitt, Harrison Collin. "Creep and Creep-fatigue Deformation Studies in 22V and P91 Creep-strength EnhancedFerritic Steels." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555603135480185.

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Giannopoulos, Ioannis. "Creep and creep-rupture behaviour of Aramid fibres." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/252181.

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To obtain creep-rupture data at low level within a reasonably short time-scale, two accelerated techniques have been investigated. Stepped Isothermal Method (SIM) testing involves loading a single specimen, under constant load, with the temperature increased in a series of steps to accelerate the creep. Careful choice of the temperature step and step duration allow the test to be completed in about 24 hours. At each temperature step a creep curve is obtained; these are then adjusted to compensate for the different temperature levels and a creep master curve at a reference temperature is produced. In Stepped Isostress Method (SSM) testing, a similar approach is adopted but the acceleration is obtained by increasing the stress in steps while keeping the temperature constant. Additional stress provides energy to the system in an analogue of the effect of heat in SIM. In this thesis, SIM and SSM tests have been successfully applied to two slightly different aramid fibres, Kevlar 49 and Technora, for a wide range of loads (50-80% ABL). The test data are used to determine the creep and creep-rupture behaviour of the two materials. The creep master curves obtained by accelerated testing are compared with conventional creep tests at ambient conditions, and good agreement of the data is observed. A rheological model for the prediction of the creep and creep-rupture of the two fibres is established to facilitate and greatly increase the reliability of the prediction of the long-term behaviour. This investigation allows more certainty about the creep-rupture relationships for different high modulus fibres, which will in turn allow more realistic safety factors to be applied when using these materials in engineering applications.

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Books on the topic "CREBBP"

de, Villiers H. L., ed. The physics of creep: Creep and creep-resistant alloys. London: Taylor & Francis, 1995.

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Creep. Berlin: Aufbau, 2022.

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Creep. New York: Gallery Books, 2011.

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Johanknecht, Susan. Creep. London: Gefn Press, 1997.

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Betten, Josef. Creep Mechanics. Berlin, Heidelberg: Springer Berlin Heidelberg, 2002. http://dx.doi.org/10.1007/978-3-662-04971-6.

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Battin, B. W. The Creep. New York: Fawcett Gold Medal, 1986.

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service), SpringerLink (Online, ed. Creep Mechanics. Berlin, Heidelberg: Springer-Verlag Berlin Heidelberg, 2008.

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Betten, Josef. Creep Mechanics. Berlin, Heidelberg: Springer Berlin Heidelberg, 2002.

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T, Foster John. The Creep. London: Eureka, 1994.

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Pelham, David. Crawlies creep. New York, N.Y: Dutton, 1996.

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Book chapters on the topic "CREBBP"

John, Vernon. "Creep and Creep Testing." In Testing of Materials, 78–89. London: Macmillan Education UK, 1992. http://dx.doi.org/10.1007/978-1-349-21969-8_7.

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Migoń, Piotr. "Creep." In Encyclopedia of Natural Hazards, 129–30. Dordrecht: Springer Netherlands, 2013. http://dx.doi.org/10.1007/978-1-4020-4399-4_79.

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Verruijt, Arnold. "Creep." In An Introduction to Soil Mechanics, 157–62. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-61185-3_19.

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Perron, J. Taylor. "Creep." In Encyclopedia of Planetary Landforms, 1–4. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4614-9213-9_88-1.

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Chawla, Nikhilesh, and Krishan K. Chawla. "Creep." In Metal Matrix Composites, 283–309. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-9548-2_9.

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Gooch, Jan W. "Creep." In Encyclopedic Dictionary of Polymers, 177–78. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-1-4419-6247-8_3053.

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Tadros, Tharwat. "Creep." In Encyclopedia of Colloid and Interface Science, 208–9. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-642-20665-8_59.

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Sabour, Mohammad Hossein. "Creep." In Encyclopedia of Tribology, 618–27. Boston, MA: Springer US, 2013. http://dx.doi.org/10.1007/978-0-387-92897-5_291.

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Shah, Dilip, and Eugene Lee. "Creep." In Intermetallic Compounds - Principles and Practice, 297–324. Chichester, UK: John Wiley & Sons, Ltd, 2002. http://dx.doi.org/10.1002/0470845856.ch16.

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Lambiel, Christophe, Reynald Delaloye, and Isabelle Gärtner-Roer. "Creep." In Encyclopedia of Earth Sciences Series, 163–65. Dordrecht: Springer Netherlands, 2011. http://dx.doi.org/10.1007/978-90-481-2642-2_78.

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Conference papers on the topic "CREBBP"

Green, Michael R. "Abstract IA25: CREBBP: Not all mutations are created equal." In Abstracts: AACR Virtual Meeting: Advances in Malignant Lymphoma; August 17-19, 2020. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/2643-3249.lymphoma20-ia25.

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Chang, Yunchao, David W. Woessner, Wenwei Lin, Taosheng Chen, Beisi Xu, Yiping Fan, Haiyan Tan, et al. "Abstract IA12: Modeling and targeting CREBBP mutations in relapsed acute lymphoblastic leukemia." In Abstracts: AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; December 3-6, 2017; Atlanta, Georgia. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.pedca17-ia12.

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Zhou, Ting, Ziming Cheng, Christi Walter, and Vivienne I. Rebel. "Abstract B27: Novel insights into the pathogenesis of myelodysplastic syndrome using Crebbp+/- mice." In Abstracts: AACR Special Conference: Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; November 3-6, 2013; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.pedcan-b27.

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Pickering, Curtis, Manish Kumar, Kathleen Bridges, Tongxin Xie, David Molkentine, Aakash Sheth, Liang Yang, et al. "Abstract 2925: Targeting histone acetyltransferase (HAT) function for synthetic cytotoxicity in CREBBP/EP300 mutant tumors." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2925.

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Peck, Barrie, Philip J. Bland, Patty T. Wai, Hannah Cottom, Sarah L. Maguire, Eamonn Morrison, Holly E. Barker, et al. "Abstract 788: Modeling tumor microenvironmental heterogeneity identifies CREBBP as a novel tumor suppressor in breast cancer." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-788.

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Li, Jiaping, Wenzhe Fan, Yue Zhao, Miao Xue, Tingting Chen, Wenzhuan Xie, and Mengli Huang. "Abstract 2236: A Pan-cancer Analysis of CREBBP as a potential predictor for immune checkpoint therapy." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-2236.

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Natrajan, Rachael. "Abstract P3-10-17: CREBBP alterations lead to CDK4/6 inhibitor sensitivity in triple negative breast cancer." In Abstracts: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.sabcs19-p3-10-17.

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Kumar, Manish, Kathleen Bridges, David Molkentine, Liangpeng Yang, Aakash Sheth, Raymond Meyn, Mitchell Frederick, Jeffrey Myers, Curtis Pickering, and Heath D. Skinner. "Abstract 978: In vivo shRNA screening identifies synthetic cytotoxicity in CREBBP/EP300 mutant head and neck cancer." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-978.

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Spriano, Filippo, Eugenio Gaudio, Chiara Tarantelli, Gaetanina Golino, Luciano Cascione, Emanuele Zucca, Anastasios Stathis, Francis Giles, and Francesco Bertoni. "Abstract 3829: NEO1132 and NEO2734, novel dual bromodomain inhibitors of both BET and CREBBP/EP300, compared to single BET or CREBB/EP300 inhibitors in diffuse large B cell lymphoma." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-3829.

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Reports on the topic "CREBBP"

Thembeka Ncube, Ayanda, and Antonio Bobet. Use of Recycled Asphalt. Purdue University, 2021. http://dx.doi.org/10.5703/1288284317316.

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The term Reclaimed Asphalt Pavement (RAP) is used to designate a material obtained from the removal of pavement materials. RAP is used across the US in multiple applications, largely on asphalt pavement layers. RAP can be described as a uniform granular non-plastic material, with a very low percentage of fines. It is formed by aggregate coated with a thin layer of asphalt. It is often used mixed with other granular materials. The addition of RAP to aggregates decreases the maximum dry unit weight of the mixture and decreases the optimum water content. It also increases the Resilient Modulus of the blend but decreases permeability. RAP can be used safely, as it does not pose any environmental concerns. The most important disadvantage of RAP is that it displays significant creep. It seems that this is caused by the presence of the asphaltic layer coating the aggregate. Creep increases with pressure and with temperature and decreases with the degree of compaction. Creep can be mitigated by either blending RAP with aggregate or by stabilization with chemical compounds. Fly ash and cement have shown to decrease, albeit not eliminate, the amount of creep. Mechanical stabilizing agents such as geotextiles may also be used.

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Wright, Jill K., Laura J. Carroll, and Richard N. Wright. Creep and Creep-Fatigue of Alloy 617 Weldments. Office of Scientific and Technical Information (OSTI), August 2014. http://dx.doi.org/10.2172/1168621.

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Dr. F. W. Brust, Dr. G. M. Wilkowski, Dr. P. Krishnaswamy, and Mr. Keith Wichman. Creep and Creep-Fatigue Crack Growth at Structural Discontinuities and Welds. Office of Scientific and Technical Information (OSTI), January 2010. http://dx.doi.org/10.2172/974286.

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Ubic, Rick, Darryl Butt, and William Windes. Irradiation Creep in Graphite. Office of Scientific and Technical Information (OSTI), March 2014. http://dx.doi.org/10.2172/1128528.

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JL Bump and RF Luther. Biaxial Creep Specimen Fabrication. Office of Scientific and Technical Information (OSTI), February 2006. http://dx.doi.org/10.2172/884675.

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Frank E. Goodwin. Creep Resistant Zinc Alloy. Office of Scientific and Technical Information (OSTI), December 2002. http://dx.doi.org/10.2172/809087.

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Kennedy, C. R. (Irradiation creep of graphite). Office of Scientific and Technical Information (OSTI), December 1990. http://dx.doi.org/10.2172/6410826.

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Huneault, P. A. Relaxation Solutions For Creep. Natural Resources Canada/ESS/Scientific and Technical Publishing Services, 1991. http://dx.doi.org/10.4095/132481.

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Rabiei, Afsaneh, Paul Bowen, Amrita Lall, Siddhartha Sarkar, Swathi Upadhyay, Suyang Yu, Jin Yan, Rengen Ding, and Hangyue Li. Creep and Creep-Fatigue Crack Growth Mechanisms in Alloy709 — NEUPRC-3.2 (Final Report). Office of Scientific and Technical Information (OSTI), April 2019. http://dx.doi.org/10.2172/1511040.

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Barinakumar, Aishwarya, Joseph Bracci, Zachary Grasley, Joshua Hogancamp, Lauren Kelly, Benjamin Spencer, and Christa Torrence. EXPERIMENTALLY VALIDATED COMPUTATIONAL MODELING OF CREEP AND CREEP-CRACKING FOR NUCLEAR CONCRETE STRUCTURES. Office of Scientific and Technical Information (OSTI), October 2020. http://dx.doi.org/10.2172/1700505.

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