Academic literature on the topic 'CREBBP mutations'
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Journal articles on the topic "CREBBP mutations"
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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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Schroers-Martin, Joseph G., Joanne Soo, Gabriel Brisou, Florian Scherer, David M. Kurtz, Brian Sworder, Michael S. Khodadoust, et al. "Recurrent Crebbp Mutations in Follicular Lymphoma Appear Localized to the Committed B-Cell Lineage." Blood 136, Supplement 1 (November 5, 2020): 30–31. http://dx.doi.org/10.1182/blood-2020-142761.
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Background: Follicular lymphoma (FL) is genetically characterized by translocations involving the BCL2 locus on chromosome 18q21. However, up to 70% of healthy individuals also carry detectable t(14;18)-positive cells, suggesting BCL2 translocation is critical but not sufficient for FL development. Chromatin modifying genes (CMGs) including KMT2D, CREBBP, EZH2, and EP300 are almost ubiquitously mutated in FL. We previously reported the direct characterization by ultra-deep sequencing of pre-diagnostic blood and tissue specimens from 19 subjects who ultimately developed FL. CREBBP lysine acetyltransferase (KAT) domain mutations were the most commonly observed precursor lesions, detected in blood a median of 7.5 years before diagnosis in patients developing FL (8/19, 42%) but not in healthy adults with or without detected BCL2 translocations (0/13, p=0.01 and 0/20, p<0.001, respectively) (Schroers-Martin et al, ASH Annual Meeting 2017). While the BCL2 translocation is thought to occur in pre-B-cell precursors in the bone marrow, the high prevalence of CMG mutations raises the possibility that, analogous to myeloid age-related clonal hematopoiesis, such early lesions could occur in hematopoietic stem cells (HSCs) rather than in the committed B-cell lineage. Methods: To address this question of mutational hierarchy, we studied blood, bone marrow aspirate, and lymph node samples from 6 patients with CREBBP or KMT2D mutations in their FL tumor. We analyzed flow-sorted purified hematopoietic cell populations by deep sequencing, including isotype-specific mature B-cell, mature T-cell, and precursor populations encompassing HSCs and common lymphoid progenitors (CLPs). Patients additionally underwent routine clinical sequencing of tumor biopsy and marrow specimens. Results: Bulk sequencing of a diagnostic bone marrow aspirate from patient FL002 revealed a CREBBP mutation concordant with FL tumor biopsy. To ascertain the population bearing this mutation, we sorted to high purity viable marrow aspirate cells (Fig. A). The CREBBP mutation was confirmed in the mature B-cell compartment at an AF of 40.3% but was not detected in other cell populations. To validate this finding, a similar sorting strategy was employed on viable bone marrow aspirate or peripheral blood samples from another 4 FL patients bearing CREBBP mutations (Fig B). In each case, CREBBP was absent from the CD34+ precursor population. In patient CIML004 a characteristic KMT2D stop mutation was likewise absent in precursors. An atypical case sheds additional light on the localization of early FL mutations. Patient LYM267 was diagnosed with Grade 1-2 FL bearing CREBBP and NRAS mutations. Eight years into a prolonged remission after chemoimmunotherapy, he developed cutaneous and gingival myeloid sarcoma without radiographic or histopathological evidence of FL recurrence. While the CREBBP mutation was not detected in myeloid sarcoma or bone marrow biopsies, concordant NRAS mutations and clonal VDJ rearrangements were seen in all 3 compartments (Fig. C). This unusual clonal lineage favors the occurrence of the CREBBP mutation later than the branch point between morphologically distinct lymphoid and myeloid tumors, likely in the committed B-cell lineage after pre-BCR rearrangements (Fig D). Conclusions: HSCs are believed to be the cell of origin in several lymphoid leukemias, and mouse models have demonstrated lymphoma development with induced CREBBP lesions in HSCs (Horton et al Nat Cell Bio 2017). However, in sorted hematopoietic cell populations from marrow and peripheral blood, we observed CREBBP mutations in B-cell lineages but never in CD34+/CD20- precursor populations or paired lymphoid/myeloid disease. Our data therefore are not in support of HSCs as a precursor reservoir in FL. Given that cells harboring the t(14;18) translocation in healthy individuals appear derived from the germinal center, recurrent mutations in CREBBP are likely to occur after the pre-B-cell stage. Figure Disclosures Kurtz: Genentech: Consultancy; Foresight Diagnostics: Other: Ownership; Roche: Consultancy. Khodadoust:Kyowa Kirin: Consultancy; Seattle Genetics: Consultancy. Nadel:Innate Pharma: Research Funding; Institut Roche: Research Funding. Diehn:RefleXion: Consultancy; Varian Medical Systems: Research Funding; Illumina: Research Funding; Roche: Consultancy; BioNTech: Consultancy; AstraZeneca: Consultancy. Roulland:Celgene/BMS: Research Funding; Roche: Honoraria. Alizadeh:Pharmacyclics: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Chugai: Consultancy; Gilead: Consultancy; Pfizer: Research Funding; Roche: Consultancy.
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Tokunaga, Kenji, Shunichiro Yamaguchi, Eisaku Iwanaga, Tomoko Nanri, Taizo Shimomura, Hitoshi Suzushima, Mitsuya Hiroaki, and Norio Asou. "Crebbp HAT Domain Mutations Are Frequently Detected in Adult Acute Lymphoblastic Leukemia." Blood 120, no. 21 (November 16, 2012): 1419. http://dx.doi.org/10.1182/blood.v120.21.1419.1419.
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Abstract Abstract 1419 Aims: Molecular pathogenesis of acute lymphoblastic leukemia (ALL) has largely been verified in pediatric patients and the identification of genetic alterations have contributed to stratifying therapeutic applications. In adult patients with ALL, cytogenetic and genetic abnormalities have not sufficiently been elucidated and therapeutic improvement has been hindered. CREB binding protein (CREBBP) is a transcriptional coactivator that interacts with a diverse range of transcription factors and regulates transcription by histone acetylation in hematopoiesis. Mutations of the CREBBP gene are recently found in approximately 2–4% of pediatric patients with ALL. Especially in relapsed cases, the mutations prevail (18–63%) and are possible markers for prediction of relapse in pediatric ALL. In adult patients with ALL, the clinical significance of CREBBP mutations remains to be determined. Here we examined adult ALL patients in an attempt to determine the incidence, clinical characteristics and prognostic impact of the CREBBP mutations. Methods: We investigated 71 adult patients with newly diagnosed ALL treated with JALSG protocols between 1986 and 2010. Age ranged from 15 to 86 years, with a median of 54 years. CREBBP mutations are dominantly identified in histone acetyltransferase (HAT) domain. HAT domain in the CREBBP gene was amplified with RT-PCR using RNA isolated from the peripheral blood or bone marrow mononuclear cells at diagnosis and was subjected to direct sequencing. We compared clinical profiles between patients with and without CREBBPHAT domain mutations. This study was approved by the Institutional Review Boards and informed consent was obtained from each patient according to guidelines based on the revised Declaration of Helsinki. Results: CREBBP HAT domain mutations were detected in 8 of 71 (11.3%) patients: one nonsense mutation, five insertion mutations with frameshifts, and five missense mutations. Two patients harbored biallelic mutations. The mutations at diagnosis in adult patients were seen more frequently than those in pediatric patients ever reported. Such mutations were not completely identical to those detected in pediatric ALL, but were seen in the region within the HAT domain, indicating that such mutations are loss-of-function mutations. The mutations were found in both B-cell (6/53: 11.3%) and T-cell (1/9: 11.1%) ALL, and distributed in patients harboring IKZF1 alterations (3/31: 9.7%) or the BCR-ABL fusion gene (2/19: 10.5%). There were no statistical difference in age, sex, leukocyte, platelet counts and complete remission rate between patients with and without the CREBBP HAT domain mutations. Patients with the mutations had a trend with worse cumulative incidence of relapse (P=0.4637), relapse-free survival (P=0.4195) and OS (P=0.2349) compared to patients lacking the mutations, but statistical significance was not detected in this small cohort. Conclusions: CREBBP HAT domain mutations at diagnosis in adult ALL are found more frequently than in pediatric ALL. This may be one of the mechanisms that adult ALL has been associated with poor OS compared with pediatric ALL. In this study, CREBBP HAT domain mutations were observed in various subtypes of ALL: both B-cell and T-cell ALL, and both Philadelphia chromosome positive and negative ALL. In pediatric ALL, CREBBP mutations were frequently seen in relapsed patients but not in previously untreated patients. These observations suggest that CREBBP mutations play an important role in an additional late event(s) leading to the development and progression of ALL. Our study implies the possibility that mutations of the CREBBP gene are associated with the pathogenesis and prognostic marker of adult ALL and represent specific epigenetic modifiers in adult ALL, serving as potential therapeutic targets. Disclosures: No relevant conflicts of interest to declare.
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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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Chafai Elalaoui, Siham, Wiam Smaili, Julien Van-Gils, Patricia Fergelot, Ilham Ratbi, Mariam Tajir, Benoit Arveiler, Didier Lacombe, and Abdelaziz Sefiani. "Clinical description and mutational profile of a Moroccan series of patients with Rubinstein Taybi syndrome." African Health Sciences 21, no. 2 (August 2, 2021): 960–67. http://dx.doi.org/10.4314/ahs.v21i2.58.
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Background: Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is a rare autosomal dominant developmental disorder with an estimated prevalence of one case per 125,000 live births. RSTS is characterized by typical face, broad thumbs and halluces, short stature, and intellectual disability. Facial dysmorphy is characteristic with microcephaly, low frontal hairline, arched eyebrows, long eyelashes, convex profile of nose, narrow palate, and micrognathia. RSTS is mainly due to mutations or microdeletions of the CREBBP gene (about 60%) and more rarely of the EP300 gene (8%).
Objective: Clinical description and identification of mutations of patients with Rubinstein Taybi syndrome.
Methods: PCR and direct sequencing of CREBBP gene.
Results: We report here, the clinical and molecular data of a series of six Moroccan patients with a phenotype of RSTS. The molecular study of the major gene CREBBP (by Sanger Sequencing followed by CGH array, if sequence normal) revealed point mutations in five patients. For the sixth patient, CGH array revealed a microdeletion carrying the CREBBP gene. Through this work, we emphasize the importance of clinical expertise in the diagnosis, management and genetic counseling in Rubinstein Taybi syndrome.
Keywords: Rubinstein Taybi syndrome; CREBBP gene; mutation; Moroccan.
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Green, Michael R., Shingo Kihira, Chih Long Liu, Ramesh V. Nair, Raheleh Salari, Andrew J. Gentles, Jonathan Irish, et al. "Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation." Proceedings of the National Academy of Sciences 112, no. 10 (February 23, 2015): E1116—E1125. http://dx.doi.org/10.1073/pnas.1501199112.
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Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.
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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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Mullighan, Charles, Jinghui Zhang, Lawryn H. Kasper, Stephanie Lerach, Debbie Payne-Turner, Letha A. Phillips, J. Racquel Collins-Underwood, et al. "CREBBP Mutations In Relapsed Acute Lymphoblastic Leukemia." Blood 116, no. 21 (November 19, 2010): 413. http://dx.doi.org/10.1182/blood.v116.21.413.413.
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Abstract Abstract 413 Relapsed acute lymphoblastic leukemia (ALL) is a leading cause of death due to disease in young people, but the biologic determinants of treatment failure remain poorly understood. To identify novel sequence mutations contributing to relapsed in ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. The cohort included B-progenitor ALL with high hyperdiploidy (N=3), TCF3-PBX1 (N=1), ETV6-RUNX1 (N=3), rearrangement of MLL (N=3), BCR-ABL1 (N=3), and low hyperdiploid, pseudodiploid, or miscellaneous karyotypes (N=10). This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including mutations in the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 63 diagnosis-relapse cases and 200 acute leukaemia cases that did not relapse found that 19% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase (HAT) CREB-binding protein (CBP). The mutations were either present at diagnosis, acquired at relapse, or duplicated to homozygosity at the time of relapse. Moreover, several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations confer a selective advantage and promote resistance to therapy. The mutations either resulted in truncated alleles or deleterious substitutions in highly conserved residues of the HAT domain. To examine the functional consequences of the mutations, we introduced wild type or mutant Crebbp alleles into Cbp/Ep300flox/flox murine embryonic fibroblasts, (dKO MEFs), and examined histone acetylation, expression of CREBBP target genes, and cellular proliferation. The HAT domain mutations resulted in impaired acetylation of the key Crebbp substrate, H3K18, and resulted in impaired transcriptional regulation of multiple CREBBP targets and pathways, including cAMP, dsRNA and dexamethasone responsive genes. The latter observation suggests that CREBBP mutations may directly result in resistance to corticosteroid therapy, which is a hallmark of high risk ALL. Together, these data these results extend the landscape of genetic alterations in leukemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL. Disclosures: Pui: EUSA Pharma: Honoraria; Enzon: Honoraria; Sanofi-Aventis: Honoraria.
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Tokunaga, Kenji, Shunichro Yamaguchi, Taizo Shimomura, Hitoshi Suzushima, Yutaka Okuno, Hiroaki Mitsuya, and Norio Asou. "Accumulation Of Gene Alterations Of TP53, Crebbp and IKZF1 Is a Prognostic Factor In Adult Acute Lymphoblastic Leukemia." Blood 122, no. 21 (November 15, 2013): 1386. http://dx.doi.org/10.1182/blood.v122.21.1386.1386.
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Abstract Aims Mutations of the genes associating with cell differentiation or proliferation are recognized as factors of tumorigenesis or prognosis in hematological malignancies. In pediatric acute lymphoblastic leukemia (ALL), alterations of IKZF1 (a factor of lymphocyte differentiation), TP53 (a cell cycle regulator) and CREBBP (a histone modifier) are found as possible prognostic markers for stratification of treatments. On the other hand, in adult ALL, clinical significance of such alterations remains to be determined. In the present work, we examined whether the mutations in those genes affected the incidence and prognosis in adult ALL patients. Methods We investigated 87 adult patients with newly diagnosed ALL treated with JALSG protocols between 1986 and 2011. Age ranged from 15 to 86 years, with a median of 51 years. We obtained cDNA and genomic DNA from the peripheral blood or bone marrow mononuclear cells at diagnosis. CREBBP mutations are dominantly identified in the histone acetyltransferase (HAT) domain. HAT domain in the CREBBP gene was amplified by PCR using cDNA and was subjected to direct sequencing. Additionally other histone modifiers, EZH2, EED, and UTX, were sequenced as the same as in CREBBP. TP53 exons 5 – 8 and 10, in which mutations were commonly reported, were sequenced using genomic DNA. We amplified IKZF1 using RT-PCR for detecting aberrant dominant negative isoforms: Ik6 and Ik10. Genomic deletions of IKZF1 were assessed with RQ-PCR or genomic DNA PCR. We compared clinical profiles between patients with and without such gene mutations. The present study was approved by the Institutional Review Boards and informed consent was obtained from each patient according to guidelines based on the revised Declaration of Helsinki. Results In 87 adult patients with ALL, alterations of CREBBP, EED, TP53 and IKZF1 were detected in 7 (9.5%), 3 (4.8%), 6 (6.9%) and 42 (50%), respectively. None of EZH2 and UTX mutation was found. The alterations of CREBBP and IKZF1 at diagnosis in adult patients were more frequent than those in pediatric patients ever reported. Some gene mutations were not found frequently. Each gene mutation per se did not significantly affect prognosis. We tried to predict the prognosis by scoring gene mutations and chromosomal abnormalities. Philadelphia chromosome (Ph) has great impact to prognosis of patients with ALL. We scored the number of mutated genes and Ph for each patient. As the score was higher, adult patients with ALL had poorer relapse-free survival (P=0.0439) and OS (P=0.4819), but statistical significance was not detected in this small cohort. Conclusions and Discussion Single gene mutations, such as IKZF1, can predict the prognosis in pediatric ALL. In adult ALL, however, only few gene mutations are reported to be promising prognostic factors which have impacts to treatment outcomes. Scoring system may be a useful method for predicting prognosis and stratifying treatment in adult ALL. Our study implies the possibility that a variety and heterogeneity of genetic alterations in adult ALL are associated with the pathogenesis for treatment resistance and prognostic marker of adult ALL. Disclosures: No relevant conflicts of interest to declare.
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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.
Dissertations / Theses on the topic "CREBBP mutations"
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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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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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Mehmood, Tahir. "Unraveling molecular, cellular and cognitive defects in the mouse model for mental retardation caused by Rsk2 gene mutation." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00868704.
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Coffin-Lowry Syndrome (CLS), an X-linked form of intellectual disability, is caused by mutations of the RPS6KA3 gene encoding the growth factor regulated kinase RSK2. To understand the consequences of RSK2 deficiency in the hippocampus we performed a comparison of the hippocampal gene expression profiles from Rsk2-KO and WT mice. It revealed differentialexpression of 100 genes, encoding proteins acting in various biological pathways. We further analyzed the consequences of deregulation of one of these genes, Gria2 encoding GluR2, a subunit of the glutamate AMPAR. An abnormal two-fold increased expression of GluR2 was found in the hippocampus of Rsk2-KO mice. Electrophysiology studies showed a reduction of basal AMPAR and NMDAR mediated transmission, in the hippocampus of Rsk2-KO mice. Activity of ERK1/2 was also abnormally increased in the adult hippocampus of Rsk2-KO mice. P-Sp1 level was also significantly higher in RSK2 deficient cells. Together, my results suggested that over expression of GluR2 in RSK2 deficient cells, is caused by increased Sp1 transcriptional activity on the Gria2 gene, which, itself, is the result of ERK1/2 increased signaling.
Books on the topic "CREBBP mutations"
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Johnston, Michael V. Coffin-Lowry Syndrome. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0057.
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Coffin-Lowry syndrome (CLS) is a relatively rare (1:50,000-100,000 incidence) sex-linked neurodevelopmental disorder that includes severe intellectual disability, dysmorphic features including facial and digital abnormalities, growth retardation, and skeletal changes. Most cases are sporadic with only 20% to 30% of cases having an additional family member. CLS is caused by variable loss of function mutations in the RPS6KA3 gene that maps to Xp22.2 and codes for the hRSK2 S6 kinase that phosphorylates the transcription factor CREB (cAMP response element binding protein) as well as other nuclear transcription factors. Phosphorylated CREB (pCREB) plays a major role in memory formation in fruit flies and mammals by activating specific genes through epigenetic histone acetylation.
Conference papers on the topic "CREBBP mutations"
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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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De Carvalho Ribeiro Júnior, Egidio, Omar Andres Carmona Cortes, and Osvaldo Ronald Saavedra. "A Parallel Mix Self-Adaptive Genetic Algorithm for Solving the Dynamic Economic Dispatch Problem." In Simpósio Brasileiro de Sistemas Elétricos - SBSE2020. sbabra, 2020. http://dx.doi.org/10.48011/sbse.v1i1.2499.
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The purpose of this paper is to propose a parallel genetic algorithm that has adaptive and self-adaptive characteristics at the same time for solving the Dynamic Economic Dispatch (DED) problem that is a challenging problem to solve. The algorithm selects the proper operators (using adaptive features) and probabilities (using the self-adaptive code) that produce the most fittable individuals. Regarding operations, the choice is made between four different types of crossover: simple, arithmetical, non-uniform arithmetical, and linear. Concerning mutation, we used four types of mutations (uniform, non-uniform, creep, and enhanced apso). The choice is made scholastically, which is uniform at the beginning of the algorithm, being adapted as the AG executes. The crossover and mutation probabilities are coded into the genes, transforming this part of the algorithm into self-adaptive. The multicore version was coded using OpenMP. An ANOVA test, along with a Tukey test, proved that the mixed self-adaptive algorithm works better than both: a random algorithm, which chooses operators randomly, and a combination of operators set previously in the DED optimization. Regarding the performance of the parallel approach, results have shown that a speedup of up to 3.19 can be reached with no loss in the quality of solutions.
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Kim, Dong-Wook, Keebeom Kim, Colin T. Dunn, and Kwon-Sik Park. "Abstract PR09: Alterations in cell junctions and neuroendocrine differentiation are key early steps in Crebbp/Ep300 mutation-driven SCLC development." In Abstracts: Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; January 8-11, 2018; San Diego, CA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1557-3265.aacriaslc18-pr09.
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Akmandor, Ibrahim Sinan, O¨zhan O¨ksu¨z, Sec¸kin Go¨kaltun, and Melih Han Bilgin. "Genetic Optimization of Steam Injected Gas Turbine Power Plants." In ASME Turbo Expo 2002: Power for Land, Sea, and Air. ASMEDC, 2002. http://dx.doi.org/10.1115/gt2002-30416.
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A new methodology is developed to find the optimal steam injection levels in simple and combined cycle gas turbine power plants. When steam injection process is being applied to simple cycle gas turbines, it is shown to offer many benefits, including increased power output and efficiency as well as reduced exhaust emissions. For combined cycle power plants, steam injection in the gas turbine, significantly decreases the amount of flow and energy through the steam turbine and the overall power output of the combined cycle is decreased. This study focuses on finding the maximum power output and efficiency of steam injected simple and combined cycle gas turbines. For that purpose, the thermodynamic cycle analysis and a genetic algorithm are linked within an automated design loop. The multi-parameter objective function is either based on the power output or on the overall thermal efficiency. NOx levels have also been taken into account in a third objective function denoted as steam injection effectiveness. The calculations are done for a wide range of parameters such as compressor pressure ratio, turbine inlet temperature, air and steam mass flow rates. Firstly, 6 widely used simple and combined cycle power plants performance are used as test cases for thermodynamic cycle validation. Secondly, gas turbine main parameters are modified to yield the maximum generator power and thermal efficiency. Finally, the effects of uniform crossover, creep mutation, different random number seeds, population size and the number of children per pair of parents on the performance of the genetic algorithm are studied. Parametric analyses show that application of high turbine inlet temperature, high air mass flow rate and no steam injection lead to high power and high combined cycle thermal efficiency. On the contrary, when NOx reduction is desired, steam injection is necessary. For simple cycle, almost full amount of steam injection is required to increase power and efficiency as well as to reduce NOx. Moreover, it is found that the compressor pressure ratio for high power output is significantly lower than the compressor pressure ratio that drives the high thermal efficiency.