Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia.

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.

• Authors: M A Dawson, E J Gudgin, S J Horton, G Giotopoulos, E Meduri, S Robson, E Cannizzaro, H Osaki, M Wiese, S Putwain, C Y Fong, C Grove, J Craig, A Dittmann, D Lugo, P Jeffrey, G Drewes, K Lee, L Bullinger, R K Prinjha, T Kouzarides, G S Vassiliou, B J P Huntly
• Journal: Leukemia (Leukemia) Vol. 28 Issue 2 Pg. 311-20 (Feb 2014) ISSN: 1476-5551 [Electronic] England
• PMID: 24220271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BRD4 protein, human
• Cell Cycle Proteins
• NPM1 protein, human
• Npm1 protein, mouse
• Nuclear Proteins
• Transcription Factors
• Nucleophosmin
• Benzodiazepines
• molibresib

Topics

• Animals
• Benzodiazepines (administration & dosage, 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, genetics, metabolism, mortality)
• Mice
• Nuclear Proteins (genetics, metabolism)
• Nucleophosmin
• Transcription Factors (metabolism)
• Transcription, Genetic
• Transcriptional Activation
• Xenograft Model Antitumor Assays