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)
Leukemia, Myeloid, Acute/genetics , Neoplasms, Second Primary/genetics , Oncogene Proteins, Fusion/genetics , Polymorphism, Genetic , Translocation, Genetic , Adult , Aged , Chromosomes, Human, Pair 16 , Chromosomes, Human, Pair 8 , DNA Repair/genetics , Humans , Inactivation, Metabolic/genetics , Middle AgedABSTRACT
Bone marrow aspiration and biopsy can be a painful procedure. Sedation techniques may make this investigation more acceptable to patients, but have the potential to cause life-threatening complications, as well as requiring additional staff and equipment for safe administration. We assessed the use of Entonox, a 50 : 50 mix of nitrous oxide and oxygen, as a sedation and analgesic agent, and compared it to previous experience with the intravenous (i.v.) benzodiazepine midazolam. Patients' perception of pain, and both the operator and patient's views on the ease of the procedure and safety factors were recorded. Twenty-two patients who had previously required i.v. midazolam sedation (16), or who requested sedation (6) were studied. Fifteen of 16 (94%) found Entonox better or equal to midazolam, and only one patient (6%) found it worse. There were no serious adverse events due to Entonox. We have shown, in this small group of patients, that Entonox is an effective, safe alternative to intravenous midazolam for sedation during bone marrow biopsy, and is considered acceptable by both patients and staff. It has the major advantage that no additional staff or facilities are required for safe administration or monitoring the patient during or after the procedure.
