Functional interdependence of BRD4 and DOT1L in MLL leukemia.
Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Omer
O
Gilan
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Enid Y N
EY
Lam
Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Heidelberg, Germany.
Isabelle
I
Becher
Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.
Dave
D
Lugo
The Gurdon Institute, University of Cambridge, Cambridge, UK.
Ester
E
Cannizzaro
Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Heidelberg, Germany.
Gerard
G
Joberty
Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Heidelberg, Germany.
Aoife
A
Ward
The Gurdon Institute, University of Cambridge, Cambridge, UK.
Meike
M
Wiese
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.|Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Chun Yew
0000-0001-5773-103X
CY
Fong
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Sarah
S
Ftouni
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Dean
D
Tyler
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Kym
K
Stanley
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Laura
L
MacPherson
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Chen-Fang
CF
Weng
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Yih-Chih
YC
Chan
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Margherita
M
Ghisi
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
David
D
Smil
Cancer Epigenetics DPU, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Christopher
C
Carpenter
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Peter
P
Brown
Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.
Neil
N
Garton
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
Marnie E
ME
Blewitt
The Gurdon Institute, University of Cambridge, Cambridge, UK.
Andrew J
AJ
Bannister
The Gurdon Institute, University of Cambridge, Cambridge, UK.
Tony
T
Kouzarides
Department of Haematology, Cambridge Institute for Medical Research, Cambridge, UK.|Cambridge Stem Cell Institute, Cambridge, UK.
Brian J P
BJ
Huntly
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Ricky W
RW
Johnstone
Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Heidelberg, Germany.
Gerard
G
Drewes
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.|Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.
Sarah-Jane
SJ
Dawson
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Cheryl H
CH
Arrowsmith
Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Heidelberg, Germany.
Paola
P
Grandi
Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.
Rab K
RK
Prinjha
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.|Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.
Mark A
MA
Dawson
D000107:Acetylation; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D011485:Protein Binding; D040901:Proteomics / Q000379:methods; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D002843:Chromatin; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008780:Methyltransferases; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C473477:DOT1L protein, human