5 results on '"Obeng, Esther A."'
Search Results
2. Altered RNA Processing in Cancer Pathogenesis and Therapy.
- Author
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Obeng EA, Stewart C, and Abdel-Wahab O
- Subjects
- Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Gene Expression Regulation, Neoplastic drug effects, Humans, Neoplasms drug therapy, Polyadenylation, RNA Splicing, Neoplasms genetics, RNA Processing, Post-Transcriptional drug effects, RNA, Messenger chemistry, RNA, Messenger genetics
- Abstract
Major advances in our understanding of cancer pathogenesis and therapy have come from efforts to catalog genomic alterations in cancer. A growing number of large-scale genomic studies have uncovered mutations that drive cancer by perturbing cotranscriptional and post-transcriptional regulation of gene expression. These include alterations that affect each phase of RNA processing, including splicing, transport, editing, and decay of messenger RNA. The discovery of these events illuminates a number of novel therapeutic vulnerabilities generated by aberrant RNA processing in cancer, several of which have progressed to clinical development. SIGNIFICANCE: There is increased recognition that genetic alterations affecting RNA splicing and polyadenylation are common in cancer and may generate novel therapeutic opportunities. Such mutations may occur within an individual gene or in RNA processing factors themselves, thereby influencing splicing of many downstream target genes. This review discusses the biological impact of these mutations on tumorigenesis and the therapeutic approaches targeting cells bearing these mutations., (©2019 American Association for Cancer Research.)
- Published
- 2019
- Full Text
- View/download PDF
3. Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability.
- Author
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Paolella BR, Gibson WJ, Urbanski LM, Alberta JA, Zack TI, Bandopadhayay P, Nichols CA, Agarwalla PK, Brown MS, Lamothe R, Yu Y, Choi PS, Obeng EA, Heckl D, Wei G, Wang B, Tsherniak A, Vazquez F, Weir BA, Root DE, Cowley GS, Buhrlage SJ, Stiles CD, Ebert BL, Hahn WC, Reed R, and Beroukhim R
- Subjects
- Cell Line, Tumor, Humans, Gene Dosage, Neoplasms genetics, Neoplasms pathology, Phosphoproteins genetics, RNA Splicing Factors genetics
- Abstract
Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1 , is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency.
- Published
- 2017
- Full Text
- View/download PDF
4. A Prospective Cohort Quality Improvement Study to Reduce the Time to Antibiotics for New Fever in Neutropenic Pediatric Oncology Inpatients.
- Author
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Green AL, Yi J, Bezler N, Pikman Y, Tubman VN, Obeng EA, O'Neil T, Mersereau R, Morrissey L, and Billett AL
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Electronic Health Records, Fever etiology, Humans, Infant, Infant, Newborn, Neutropenia drug therapy, Prospective Studies, Time Factors, Anti-Bacterial Agents administration & dosage, Fever drug therapy, Neoplasms complications, Neutropenia complications, Quality Improvement
- Abstract
Background: Fever and neutropenia (F&N) is a pediatric oncology emergency due to the risk of disseminated infection. Quality improvement (QI) efforts to improve time to antibiotics for F&N in the emergency department have been documented, but the issue has not been studied in the established inpatient setting., Procedure: We undertook a prospective cohort QI study to decrease time to antibiotics for neutropenic pediatric oncology inpatients with new fever to <60 min. Our key intervention was discussion of a plan in case of new fever, including antibiotic(s) to be started, for each patient on rounds. Timing for each step in the process, from fever identification to antibiotic administration, was measured through the electronic medical record for each fever event., Results: The median time to antibiotics during the 3-three month intervention study period was 76.0 min, although the distribution was skewed due to several long outliers (mean 142.5, interquartile range 51-206, range 47-593 min). Time to antibiotics was significantly shorter when a fever contingency plan was documented in the most recent note than not (mean 102 vs. 254 min, P = 0.039). Over the total 2.75 year data-collection period, the quarterly percentage of patients receiving antibiotics within 60 min has improved from 35 to 65, whereas quarterly mean time to antibiotics has improved from 99 to 50 min., Conclusions: Daily discussion of a fever contingency plan appears effective in decreasing the time to antibiotics for neutropenic pediatric oncology inpatients with new fever, likely by circumventing the need for multi-level discussion of the antibiotic plan when fever is identified., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
5. A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion
- Author
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Yin, Shanye, Gambe, Rutendo G, Sun, Jing, Martinez, Aina Zurita, Cartun, Zachary J, Regis, Fara Faye D, Wan, Youzhong, Fan, Jean, Brooks, Angela N, Herman, Sarah EM, Hacken, Elisa ten, Taylor-Weiner, Amaro, Rassenti, Laura Z, Ghia, Emanuela M, Kipps, Thomas J, Obeng, Esther A, Cibulskis, Carrie L, Neuberg, Donna, Campagna, Dean R, Fleming, Mark D, Ebert, Benjamin L, Wiestner, Adrian, Leshchiner, Ignaty, DeCaprio, James A, Getz, Gad, Reed, Robin, Carrasco, Ruben D, Wu, Catherine J, and Wang, Lili
- Subjects
Rare Diseases ,Lymphoma ,Cancer ,Genetics ,Hematology ,2.1 Biological and endogenous factors ,Aetiology ,Adenine ,Agammaglobulinaemia Tyrosine Kinase ,Alternative Splicing ,Animals ,Antineoplastic Agents ,Ataxia Telangiectasia Mutated Proteins ,B-Lymphocytes ,Cellular Senescence ,DNA Damage ,Gene Deletion ,Genetic Predisposition to Disease ,Genomic Instability ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Mice ,129 Strain ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mice ,Mutant Strains ,Mutation ,Neoplasms ,Experimental ,Phenotype ,Phosphoproteins ,Piperidines ,Protein Kinase Inhibitors ,Pyrazoles ,Pyrimidines ,RNA Splicing Factors ,Receptors ,Antigen ,B-Cell ,Signal Transduction ,Tumor Cells ,Cultured ,ATM ,BCR signaling ,CLL ,SF3B1 ,murine model ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.
- Published
- 2019
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