Publication Date:
2011-10-04
Description:
Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679520/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679520/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dawson, Mark A -- Prinjha, Rab K -- Dittmann, Antje -- Giotopoulos, George -- Bantscheff, Marcus -- Chan, Wai-In -- Robson, Samuel C -- Chung, Chun-wa -- Hopf, Carsten -- Savitski, Mikhail M -- Huthmacher, Carola -- Gudgin, Emma -- Lugo, Dave -- Beinke, Soren -- Chapman, Trevor D -- Roberts, Emma J -- Soden, Peter E -- Auger, Kurt R -- Mirguet, Olivier -- Doehner, Konstanze -- Delwel, Ruud -- Burnett, Alan K -- Jeffrey, Phillip -- Drewes, Gerard -- Lee, Kevin -- Huntly, Brian J P -- Kouzarides, Tony -- 092096/Wellcome Trust/United Kingdom -- G0800784/Medical Research Council/United Kingdom -- G116/187/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Oct 2;478(7370):529-33. doi: 10.1038/nature10509.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21964340" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line, Tumor
;
Chromatin/genetics/*metabolism
;
Chromatin Immunoprecipitation
;
Disease Models, Animal
;
Gene Expression Profiling
;
Gene Expression Regulation, Neoplastic/drug effects
;
Heterocyclic Compounds with 4 or More Rings/pharmacology/therapeutic use
;
Humans
;
Leukemia, Myeloid, Acute/*drug therapy/genetics/*metabolism/pathology
;
Mice
;
Models, Molecular
;
Multiprotein Complexes/chemistry/metabolism
;
Myeloid-Lymphoid Leukemia Protein/*metabolism
;
Oncogene Proteins, Fusion/*metabolism
;
Protein Binding/drug effects
;
Proteomics
;
Transcription Factors/*antagonists & inhibitors/*metabolism
;
Transcription, Genetic/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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