Home LiteratureArticle Details
PMID: 24220271 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Leukemia ·Vol. 28 ·No. 2 ·2014-02-00 ·Pages 311-20

Dawson MA, Gudgin EJ, Horton SJ, Giotopoulos G, Meduri E, Robson S, Cannizzaro E, Osaki H, Wiese M, Putwain S, Fong CY, Grove C, Craig J, Dittmann A, Lugo D, Jeffrey P, Drewes G, Lee K, Bullinger L, Prinjha RK, Kouzarides T, Vassiliou GS, Huntly BJ

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.

MeSH Terms
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
Chemicals
BRD4 protein, human Cell Cycle Proteins NPM1 protein, human Npm1 protein, mouse Nuclear Proteins Transcription Factors Nucleophosmin Benzodiazepines molibresib
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Dawson M A
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK [3] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge UK.
Gudgin E J
Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.
Horton S J
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
Giotopoulos G
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
Meduri E
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
Robson S
Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge UK.
Cannizzaro E
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge UK.
Osaki H
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
Wiese M
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge UK.
Putwain S
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
Fong C Y
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge UK.
Grove C
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
Craig J
Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK.
Dittmann A
Discovery Research, Cellzome AG, Heidelberg, Germany.
Lugo D
Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
Jeffrey P
Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
Drewes G
Discovery Research, Cellzome AG, Heidelberg, Germany.
Lee K
Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
Bullinger L
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Prinjha R K
Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
Kouzarides T
Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge UK.
Vassiliou G S
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
Huntly B J P
1] Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge, UK [2] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
References (31)
31 references, click to expand
  1. Common and overlapping oncogenic pathways contribute to the evolution of acute myeloid leukemias.
    Cancer Res. 2011 Jun 15;71(12):4117-29 PMID: 21505102
  2. Fast and accurate short read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2009 Jul 15;25(14):1754-60 PMID: 19451168
  3. BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
    Cell. 2011 Sep 16;146(6):904-17 PMID: 21889194
  4. BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms.
    Leukemia. 2014 Jan;28(1):88-97 PMID: 23929215
  5. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor.
    Cancer Cell. 2011 Jul 12;20(1):53-65 PMID: 21741596
  6. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.
    Nature. 2011 Oct 02;478(7370):529-33 PMID: 21964340
  7. A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF.
    Leukemia. 2009 Mar;23(3):501-9 PMID: 19005479
  8. Acute myeloid leukaemia.
    Lancet. 2006 Nov 25;368(9550):1894-907 PMID: 17126723
  9. Targeting epigenetic readers in cancer.
    N Engl J Med. 2012 Aug 16;367(7):647-57 PMID: 22894577
  10. Suppression of inflammation by a synthetic histone mimic.
    Nature. 2010 Dec 23;468(7327):1119-23 PMID: 21068722
  11. Transcription factors in myeloid development: balancing differentiation with transformation.
    Nat Rev Immunol. 2007 Feb;7(2):105-17 PMID: 17259967
  12. lumi: a pipeline for processing Illumina microarray.
    Bioinformatics. 2008 Jul 1;24(13):1547-8 PMID: 18467348
  13. Model-based variance-stabilizing transformation for Illumina microarray data.
    Nucleic Acids Res. 2008 Feb;36(2):e11 PMID: 18178591
  14. A powerful molecular synergy between mutant Nucleophosmin and Flt3-ITD drives acute myeloid leukemia in mice.
    Leukemia. 2013 Sep;27(9):1917-20 PMID: 23478666
  15. Divorcing ARF and p53: an unsettled case.
    Nat Rev Cancer. 2006 Sep;6(9):663-73 PMID: 16915296
  16. Three distinct patterns of histone H3Y41 phosphorylation mark active genes.
    Cell Rep. 2012 Sep 27;2(3):470-7 PMID: 22999934
  17. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.
    N Engl J Med. 2012 Mar 22;366(12):1079-89 PMID: 22417203
  18. Targeting MYC dependence in cancer by inhibiting BET bromodomains.
    Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16669-74 PMID: 21949397
  19. Selective inhibition of tumor oncogenes by disruption of super-enhancers.
    Cell. 2013 Apr 11;153(2):320-34 PMID: 23582323
  20. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia.
    Nat Med. 2010 Aug;16(8):903-8 PMID: 20616797
  21. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.
    Nature. 2011 Aug 03;478(7370):524-8 PMID: 21814200
  22. Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications.
    Leukemia. 2009 Oct;23(10):1731-43 PMID: 19516275
  23. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML.
    Blood. 2006 Jun 1;107(11):4514-23 PMID: 16455950
  24. Model-based analysis of ChIP-Seq (MACS).
    Genome Biol. 2008;9(9):R137 PMID: 18798982
  25. Structural consequences of nucleophosmin mutations in acute myeloid leukemia.
    J Biol Chem. 2008 Aug 22;283(34):23326-32 PMID: 18511415
  26. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.
    Nat Genet. 2002 Jan;30(1):41-7 PMID: 11731795
  27. Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice.
    Nat Genet. 2011 May;43(5):470-5 PMID: 21441929
  28. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.
    N Engl J Med. 2005 Jan 20;352(3):254-66 PMID: 15659725
  29. Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia.
    Leukemia. 2014 Jan;28(1):50-8 PMID: 23929217
  30. Detailed molecular characterisation of acute myeloid leukaemia with a normal karyotype using targeted DNA capture.
    Leukemia. 2013 Sep;27(9):1820-5 PMID: 23702683
  31. Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance.
    Blood. 2005 Aug 1;106(3):899-902 PMID: 15831697
Article Info
Journal
Leukemia
Abbr.
Leukemia
ISSN
1476-5551
DOI
10.1038/leu.2013.338
Published
2014-02-00
Epub
2013-00-13
Pages
311-20
Language
English
Region
England
NLM ID
8704895
PMCID
PMC3918873
Subset
IM
Grants
Worldwide Cancer Research · 14-1069 · United Kingdom
Wellcome Trust · 079249 · United Kingdom
Wellcome Trust · 092096 · United Kingdom
Cancer Research UK · 10827 · United Kingdom
Wellcome Trust · 095663 · United Kingdom
Wellcome Trust · 100140 · United Kingdom
External Links
PubMed source DOI: 10.1038/leu.2013.338 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2