EP-300 / Esperance Pharma - LARVOL DELTA

[VIRTUAL] Evaluation of the Different Stratification Models for POD24 Prediction in Patients with Follicular Lymphoma (ASH 2020) - "Introduction Progression of disease within 2 years after starting rituximab-chemotherapy (POD24) has been identified as a convincing adverse prognostic factor for follicular lymphoma (FL), and can serve as a clinical endpoint to identify patients at high risk of early lymphoma-related mortality...We performed CAPP-seq to detect the mutation status of the genes included in m7-FLIPI and POD24 PI (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), as well as BCL2, TNFRSF14 and TP53...Though retaining their prognostic value, the integration of mutations onto the clinical biomarker-based prognostic scores has a limited discrimination capacity for POD24. Our results prompt the investigation of: i) POD discrimination capacity of prognostic models based on molecular phenotypes (i.e. gene expression) reflecting the tumor-microenvironment milieu; ii) new models based on a combination of biomarkers capturing the most informative clinical, genetic and phenotypic features."

Clinical • IO biomarker • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • ARID1A • BCL2 • CARD11 • CREBBP • EP300 • EZH2 • FOXO1 • TP53

[VIRTUAL] Harmony Alliance Provides Novel Insights into Acute Myeloid Leukemia Based on a Pan-European NGS Data Collection (ASH 2020) - "Examining the variant allele frequency (VAF) of mutations using a Bradley-Terry analysis, we could further refine the model of clonal evolution and generate additional evidence that epigenetic driver mutations in genes affecting DNA methylation (e.g. DNMT3A, TET2, IDH1/2) are earlier events than mutations in histone modifying enzymes (e.g. KMT2D, EZH2, ASXL1, EP300), which usually occur later... Results the HARMONY AML proof-of-principle study clearly demonstrate the benefit in combining OMOP harmonized data sets within a Pan-European “Big Data for Better Outcome” platform. In accordance, the HARMONY Alliance proves that big data sets might enable us to significantly improve individual patient outcomes and thus to further individualize patient management. By the time of the ASH Annual Meeting we will present the data of our ongoing analyses, which will included findings of a validation data set comprising additional molecularly well-defined AML cases that are currently..."

Next-generation sequencing • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Transplantation • ASXL1 • CBL • DNMT3A • EP300 • EZH2 • FLT3 • IDH1 • KMT2D • KRAS • NPM1 • NRAS • PTPN11 • RUNX1 • SF3B1 • SRSF2 • STAG2 • TET2 • TP53

[VIRTUAL] Whole-Genome Analysis of Adult T-Cell Leukemia/Lymphoma (ASH 2020) - "In particular, inactivation of EP300 and immune-related molecules, such as HLA-A, HLA-B, and CD58, were associated with an increased number of mutations and SVs, especially deletions and tandem duplications...In summary, our WGS analysis not only identifies novel somatic alterations but also extends the overview of ATL genome. We also propose a new molecular classification of ATL, with its clinical relevance, which can lead to the future improvement of patient management."

Clinical • IO biomarker • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CARD11 • CDKN2A • EP300 • IKZF2 • IRF4 • PD-L1 • STAT3 • TMSB4X • TP53 • ZNF292

Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes. (PubMed, Hereditas) - "PIK3CA, RB1, FGFR3, KMT2C, MACF1, RYR2, and EP300 are differentially mutated among three immunotypes...Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD8 • EP300 • FGFR3 • MLL3 • PIK3CA • RB1 • TGFB1 • TMB

Distinct genomic profiles of gestational choriocarcinoma, a unique cancer of pregnant tissues. (PubMed, Exp Mol Med) - "We detected five driver mutations in the GCs, most of which were chromatin remodeling gene (ARID1A, SMARCD1, and EP300) mutations but not in common cancer genes such as TP53 and KRAS...Our data indicate that GCs have unique profiles of CN-LOHs, mutations and CNAs that together differentiate GCs from non-GCs. Practically, CN-LOH and CNA profiles are useful for the molecular diagnosis of GC and the selection of GC patients with poor prognosis for more intensive treatments, respectively."

Journal • Oncology • ARID1A • EP300 • KRAS • SMARCD1 • TP53

[VIRTUAL] Follicular Lymphoma Mutational Profile: Patients with mTOR Complex 1 (mTORC1) Mutations Present Differential Survival in First-Line R-CVP/R-CHOP Vs R-Bendamustine (ASH 2020) - "Very similar to previously described, top ten mutated genes were: CREBBP (75%), KMT2D (73%), BCL2 (46%), TNFRSF14 (43%), EZH2 (23%), STAT6 (21%), EP300 (19%), MEF2B (19%), IGLL5 (18%) and ARID1A (17%). Of note, we found that there is one third of FL patients that present with mutations in genes affecting the mTORC1 pathway, showing poor outcomes when treated with R-CVP/R-CHOP but not if treated with R-B. Evaluation of mTORC1 targeted therapies might be of interest in this subset of FL."

Clinical • IO Biomarker • Follicular Lymphoma • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Oncology • ARID1A • BCL2 • CREBBP • CTSS • EP300 • EZH2 • KMT2D • STAT6

[VIRTUAL] Comprehensive genomic and transcriptomic profiling of molecular subtypes reveal ancestral differences in the activity of signaling pathways between patients with African and European ancestry (SABCS 2020) - " Relative to EA TNBC, AA TNBC tumors exhibited higher mutation rates in TP53 (94% vs 86%), KMT2C (17% vs 9%), APOB (19% vs 10%), BRCA2 (11% vs 5%), EP300 (8% vs 2%), NOTCH1 (12% vs 4%), and EGFR (11% vs 4%)... These data demonstrate significant differences in breast tumor heterogeneity and mutation spectrum in TNBC and HR+/HER2- breast cancers between AA and EA patients. Ancestral differences were also observed in the activity of relevant signaling pathways for TNBC. Overall, the results identify previously unexplored pathways and molecular phenotypes of aggressive disease, providing opportunities for development of more effective biomarker informed treatment of breast cancer in diverse populations."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • APOB • BRCA2 • CCND1 • EGFR • EP300 • FGF3 • HER-2 • HRD • MLL3 • NOTCH1 • PIK3CA • RB1 • TMB • TP53

Autophagy-mediated metabolic effects of aspirin. (PubMed, Cell Death Discov) - "Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Oncology • EP300

PDL1 high expression without TP53, KEAP1 and EPHA5 mutations could better predict survival for patients with NSCLC receiving atezolizumab. (PubMed, Lung Cancer) - "Different high frequency gene mutations could be found between the patients with high and negative PDL1. PDL1 expression combined with specific gene mutation may better predict the survival for patients receiving atezolizumab."

Clinical • IO Biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • EP300 • EPHA5 • ERBB4 • FAT1 • KEAP1 • PD-L1 • SLIT2 • SMARCA4 • STK11 • TET2 • TP53

[VIRTUAL] PML-RAR Binds to the +7kb Enhancer of CEBPE and Inhibits Its Expression (ASH 2020) - "Analysis revealed that the +7kb region was marked by an open chromatin signature, accompanied by binding of a majority of hematopoietic TFs around this putative regulatory element with concurrent binding of EP300...This results in increased CEBPE expression, which in turn promotes efficient granulocytic differentiation. The findings from our study expands our current understanding of the mechanism of differentiation therapy, the role of onco-fusion proteins in inhibiting myeloid differentiation, and may provide new therapeutic approaches to many acute myeloid leukemias."

Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CEBPA • EP300 • PML • PRAM1

[VIRTUAL] Recurrent Crebbp Mutations in Follicular Lymphoma Appear Localized to the Committed B-Cell Lineage (ASH 2020) - "Chromatin modifying genes (CMGs) including KMT2D, CREBBP, EZH2, and EP300 are almost ubiquitously mutated in FL. 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."

IO Biomarker • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Sarcoma • Solid Tumor • BCL2 • CD20 • CD34 • CREBBP • EP300 • EZH2 • KMT2D • NRAS

[VIRTUAL] Characterizing Specificities of Chronic Lymphoid Leukemia Harboring a BCL2 rearrangement (ASH 2020) - "Ex vivo drug treatments included: BCL2i (inhibitor): venetoclax; MCL-1i: AZD5991, S63845 and BCLXLi: A133...No mutations in EZH2, CREBBP or EP300 were found... The genomic landscape of BCL2-R CLL is characterized by a high frequency of trisomy 12, subclonal NOTCH and RAS pathway mutations, as well as BCL2 and MLL2 mutations. Protein expression, BH3 profiling and viability assays data are consistent with nearly exclusive dependence on Bcl-2. Our data suggest that Bcl-2 inhibition should be favored over Mcl-1 inhibition in BCL2-R CLL."

IO Biomarker • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL2L1 • BCL2L11 • BIRC3 • BRAF • CREBBP • EP300 • EZH2 • FBXW7 • KMT2D • KRAS • MLL2 • MYD88 • NOTCH1 • NRAS • SF3B1 • TP53

Near-Field Measurement of Six Degrees of Freedom Mining-Induced Tremors in Lower Silesian Copper Basin. (PubMed, Sensors (Basel)) - "Long-term continuous 6-DoF measurements were conducted with the use of the R-1 rotational seismometer and EP-300 translational seismometer...Also, attenuation of rotational and translational components was qualitatively compared. Finally, the empirical formulas for seismic rotation prediction in the Lower Silesian Copper Basin were developed and validated."

Journal • Movement Disorders • EP300

TRIM27 Functions as a Novel Oncogene in Non-Triple-Negative Breast Cancer by Blocking Cellular Senescence through p21 Ubiquitination. (PubMed, Mol Ther Nucleic Acids) - "Tamoxifen (TAM) was applied to evaluate the influence of TRIM27 on chemoresistance of breast cancer cells, while co-immunoprecipitation (coIP) was performed to identify the E3 ubiquitin ligase capability of TRIM27...In addition, EP300 could enhance the expression of TRIM27 and its transcription promoter H3K27ac. TRIM27, through ubiquitination of p21, might serve as a prognostic biomarker for non-TNBC prognosis. TRIM27 functions as a novel oncogene in non-TNBC cellular processes, especially suppressing cell senescence and interfering with non-TNBC chemoresistance."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • CDKN1A • EP300 • TRIM27

CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway. (PubMed, J Exp Clin Cancer Res) - "The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • DNMT3A • EP300

Molecular Mechanism of KLF4 Up-regulating Keratin 17 Expression in Keratinocytes (PubMed, Sichuan Da Xue Xue Bao Yi Xue Ban) - "Co-IP confirmed that KLF4 and EP300 could form protein complexes. Excessive KLF4 increases the level of histone H3 acetylation in KRT17 promoter region by synergistic EP300, and mediates the over-expression of KRT17 in psoriatic lesions."

Journal • Dermatology • Immunology • Psoriasis • EP300 • KLF4

[VIRTUAL] Targeting epigenetic vulnerabilities identified from a CRISPR screen in H3.3K27M DIPG (SNO 2020) - "Secondary CRISPR validations confirmed dependencies in BMI1, CBX4, KDM1A, EZH2, EED, SUZ12, HDAC2, and EP300...Among these, an inhibitor and degrader targeting P300/CBP activity indicates a novel strategy of epigenetic therapy in DIPG. Through our combinatorial testing, we will identify a synergistic combination of epigenetic therapy for treating children diagnosed with H3.3K27M DIPG."

Diffuse Intrinsic Pontine Glioma • Gene Therapies • Glioma • Oncology • Pediatrics • Solid Tumor • BMI1 • EP300 • EZH2 • HDAC2

Upregulation of GPNCA is associated with poor prognosis through enhancement of tumor growth via regulating GSK3B. (PubMed, Sci Rep) - "The upregulation of GPNCA was partly due to enhanced H3K27ac occupancy on its promoter region via EP300 and KAT2A/GCN5...Our in vitro experiments demonstrated that GPNCA silencing inhibited tumor growth via inhibiting its nearby gene GSK3B. Taken together, these findings highlight GPNCA as a biomarker for cancer diagnosis and a potential target for future cancer drug development."

Journal • Breast Cancer • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

[VIRTUAL] Opportunities of Genome Imaging for Genetic Diagnosis in Acute Lymphoblastic Leukemia (ASH 2020) - "A t(12;22) ZNF384-EP300 fusion in a case with a normal karyotype... Bionano results were concordant with MLPA, a technique routinely used for rapid detection of key CNAs. All but one recurrent translocations identified by routine strategies were correctly identified by Bionano which failed to detect a STIL-TAL1 rearrangement in one of the two cases with this abnormality. Bionano further identified: A t(5;11) TCF7-SPI1 in a case with a failed karyotype (subsequently confirmed by another method) (Figure 1)."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • EP300 • SPI1

Generation of onco-enhancer enhances chromosomal remodeling and accelerates tumorigenesis. (PubMed, Nucleic Acids Res) - "In addition, a disruption in this chromosomal interaction prevented the histone acetyltransferase EP300 from embedding in the promoter of NTS and resulted in NTS silencing. Most importantly, in vitro and in vivo experiments showed that the ability of tumor formation was significantly suppressed via deletion of the enhancer by CRISPR-Cas9. These studies delineate a novel onco-enhancer guided epigenetic mechanism and provide a promising therapeutic concept for disease therapy."

Journal • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • EP300

Identification of a key gene module associated with glucocorticoid- induced derangement in bone mineral density in patients with asthma. (PubMed, Sci Rep) - "Among 18 hub genes in this module, we postulated that 2 genes, CREBBP and EP300, contributed to low BMD following a literature review. A novel biologic pathway identified in this study highlighted a gene module and several genes as playing possible roles in the pathogenesis of glucocorticoid- induced derangement in BMD."

Clinical • Journal • Asthma • Respiratory Diseases

[VIRTUAL] The Epigenetic Modifier EP300: A New Corner Stone in the Regulation of Both Vascular Remodeling and Right Ventricle Failure in Pulmonary Arterial Hypertension (AHA 2020) - "EP300 upregulation contributes to both pulmonary vascular remodeling and RV dysfunction seen in PAH and its inhibition represents a promising therapeutic avenue."

Fibrosis • Hypertension • Immunology • Pulmonary Arterial Hypertension • BIRC5 • EP300 • PCNA

Going up the Hill: Chromatin-based Barriers to Epigenetic Reprogramming. (PubMed, FEBS J) - "In contrast, active transcription-associated chromatin marks such as DOT1L-catalyzed H3K79 methylation, FACT-mediated histone turnover, active enhancer SUMOylation, EP300/CBP bromodomain-mediated interactions act to maintain somatic specific gene expression programs. We highlight how genetic or chemical inhibition of both types of barriers can enhance the kinetics and/or efficiency of reprogramming. Understanding the mechanisms by which these barriers function provides insight into how chromatin marks help maintain cell identity."

Journal • EP300 • KLF4 • MYC • OCT4 • SOX2

Identification of Characteristic Genomic Markers in Human Hepatoma HuH-7 and Huh7.5.1-8 Cell Lines. (PubMed, Front Genet) - "Eight genes, including DDX58 (RIG-I), BAX, EP300, and SPP1 (osteopontin), contained mutations observed only in Huh7.5.1-8 or mutations with higher frequency in Huh7.5.1-8. These mutations might be relevant to phenotypic differences between the two cell lines and may also serve as genetic markers to distinguish Huh7.5.1-8 cells from the ancestral HuH-7 cells."

Journal • Gastrointestinal Cancer • Hepatitis C Virus • Hepatocellular Cancer • Hepatology • Infectious Disease • Liver Cancer • Solid Tumor • EP300 • SPP1