ABSTRACT
Recent evidence suggests that inhibition of bromodomain and extra-terminal (BET) epigenetic readers may have clinical utility against acute myeloid leukemia (AML). Here we validate this hypothesis, demonstrating the efficacy of the BET inhibitor I-BET151 across a variety of AML subtypes driven by disparate mutations. We demonstrate that a common 'core' transcriptional program, which is HOX gene independent, is downregulated in AML and underlies sensitivity to I-BET treatment. This program is enriched for genes that contain 'super-enhancers', recently described regulatory elements postulated to control key oncogenic driver genes. Moreover, our program can independently classify AML patients into distinct cytogenetic and molecular subgroups, suggesting that it contains biomarkers of sensitivity and response. We focus AML with mutations of the Nucleophosmin gene (NPM1) and show evidence to suggest that wild-type NPM1 has an inhibitory influence on BRD4 that is relieved upon NPM1c mutation and cytosplasmic dislocation. This leads to the upregulation of the core transcriptional program facilitating leukemia development. This program is abrogated by I-BET therapy and by nuclear restoration of NPM1. Finally, we demonstrate the efficacy of I-BET151 in a unique murine model and in primary patient samples of NPM1c AML. Taken together, our data support the use of BET inhibitors in clinical trials in AML.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Transcription, Genetic , Transcriptional Activation , Animals , Benzodiazepines/administration & dosage , Benzodiazepines/pharmacology , Cell Cycle Proteins , Cell Line, Tumor , Disease Models, Animal , Drug Evaluation, Preclinical , Gene Expression Profiling , Gene Expression Regulation, Leukemic/drug effects , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Mice , Nucleophosmin , Xenograft Model Antitumor AssaysSubject(s)
Primary Prevention , Smoking Prevention , Adult , Behavior Therapy/methods , Female , Humans , Male , Motivation , Nicotine/therapeutic use , Pregnancy , Smoking/drug therapy , Smoking/psychologyABSTRACT
The present study evaluated the usefulness of the 1-min leukocyte esterase-nitrite tests in a tertiary-care hospital as a screening procedure to detect significant bacteriuria and correlated the findings with culture results. A total of 531 urine samples were reviewed, of which 484 were evaluated. Of the evaluated samples, 113 positive cultures (23.4%) were found, of which 93 (82.3%) were detected by leukocyte esterase-nitrite tests. In addition, 365 of 371 (98.4%) urine samples with negative bacterial cultures were negative in leukocyte esterase and nitrite tests.
