Journal article
Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia
MA Dawson, EJ Gudgin, SJ Horton, G Giotopoulos, E Meduri, S Robson, E Cannizzaro, H Osaki, M Wiese, S Putwain, CY Fong, C Grove, J Craig, A Dittmann, D Lugo, P Jeffrey, G Drewes, K Lee, L Bullinger, RK Prinjha Show all
Leukemia | NATURE PUBLISHING GROUP | Published : 2014
DOI: 10.1038/leu.2013.338
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 i..
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Funding Acknowledgements
Work in the Huntly laboratory is funded by Leukaemia Lymphoma Research, the Kay Kendall Leukaemia fund, the Wellcome Trust, Cancer Research UK and the Cambridge NIHR Biomedical Research Centre. Work in the Kouzarides laboratory is funded by a program grant from Cancer Research UK. MAD is a Wellcome Trust-Beit Intermediate Fellow. CYF is funded by a PhD fellowship from the Leukaemia Foundation Australia and GSV is a Wellcome Trust Senior Fellow.