PMID- 26367796
OWN - NLM
STAT- MEDLINE
DCOM- 20151019
LR  - 20240210
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 525
IP  - 7570
DP  - 2015 Sep 24
TI  - BET inhibitor resistance emerges from leukaemia stem cells.
PG  - 538-42
LID - 10.1038/nature14888 [doi]
AB  - Bromodomain and extra terminal protein (BET) inhibitors are first-in-class 
      targeted therapies that deliver a new therapeutic opportunity by directly 
      targeting bromodomain proteins that bind acetylated chromatin marks. Early 
      clinical trials have shown promise, especially in acute myeloid leukaemia, and 
      therefore the evaluation of resistance mechanisms is crucial to optimize the 
      clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem 
      and progenitor cells immortalized with the fusion protein MLL-AF9 to generate 
      several single-cell clones that demonstrate resistance, in vitro and in vivo, to 
      the prototypical BET inhibitor, I-BET. Resistance to I-BET confers 
      cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as 
      resistance to genetic knockdown of BET proteins. Resistance is not mediated 
      through increased drug efflux or metabolism, but is shown to emerge from 
      leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally 
      reduced in resistant cells, whereas the expression of key target genes such as 
      Myc remains unaltered, highlighting the existence of alternative mechanisms to 
      regulate transcription. We demonstrate that resistance to BET inhibitors, in 
      human and mouse leukaemia cells, is in part a consequence of increased 
      Wnt/beta-catenin signalling, and negative regulation of this pathway results in 
      restoration of sensitivity to I-BET in vitro and in vivo. Together, these 
      findings provide new insights into the biology of acute myeloid leukaemia, 
      highlight potential therapeutic limitations of BET inhibitors, and identify 
      strategies that may enhance the clinical utility of these unique targeted 
      therapies.
FAU - Fong, Chun Yew
AU  - Fong CY
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
AD  - Sir Peter MacCallum Department of Oncology, The University of Melbourne, East 
      Melbourne, Victoria 3002, Australia.
AD  - Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, 
      Victoria 3002, Australia.
FAU - Gilan, Omer
AU  - Gilan O
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
AD  - Sir Peter MacCallum Department of Oncology, The University of Melbourne, East 
      Melbourne, Victoria 3002, Australia.
FAU - Lam, Enid Y N
AU  - Lam EY
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
FAU - Rubin, Alan F
AU  - Rubin AF
AD  - Bioinformatics Division, The Walter &Eliza Hall Institute of Medical Research, 
      Parkville, Victoria 3052, Australia.
AD  - Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, 
      Australia.
FAU - Ftouni, Sarah
AU  - Ftouni S
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
FAU - Tyler, Dean
AU  - Tyler D
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
AD  - Sir Peter MacCallum Department of Oncology, The University of Melbourne, East 
      Melbourne, Victoria 3002, Australia.
FAU - Stanley, Kym
AU  - Stanley K
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
FAU - Sinha, Devbarna
AU  - Sinha D
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
FAU - Yeh, Paul
AU  - Yeh P
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
AD  - Sir Peter MacCallum Department of Oncology, The University of Melbourne, East 
      Melbourne, Victoria 3002, Australia.
AD  - Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, 
      Victoria 3002, Australia.
FAU - Morison, Jessica
AU  - Morison J
AD  - Department of Haematology, Cambridge Institute for Medical Research and Wellcome 
      Trust-MRC Stem Cell Institute, Cambridge CB2 0XY, UK.
FAU - Giotopoulos, George
AU  - Giotopoulos G
AD  - Department of Haematology, Cambridge Institute for Medical Research and Wellcome 
      Trust-MRC Stem Cell Institute, Cambridge CB2 0XY, UK.
FAU - Lugo, Dave
AU  - Lugo D
AD  - Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, 
      GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, 
      UK.
FAU - Jeffrey, Philip
AU  - Jeffrey P
AD  - Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, 
      GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, 
      UK.
FAU - Lee, Stanley Chun-Wei
AU  - Lee SC
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, New York 10065, USA.
FAU - Carpenter, Christopher
AU  - Carpenter C
AD  - Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville 
      Road, Collegeville, Pennsylvania 19426, USA.
FAU - Gregory, Richard
AU  - Gregory R
AD  - Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, 
      GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, 
      UK.
FAU - Ramsay, Robert G
AU  - Ramsay RG
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
AD  - Sir Peter MacCallum Department of Oncology, The University of Melbourne, East 
      Melbourne, Victoria 3002, Australia.
FAU - Lane, Steven W
AU  - Lane SW
AD  - QIMR Berghofer Medical Research Institute, University of Queensland, Brisbane, 
      Queensland 4029, Australia.
FAU - Abdel-Wahab, Omar
AU  - Abdel-Wahab O
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, New York 10065, USA.
FAU - Kouzarides, Tony
AU  - Kouzarides T
AD  - Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge CB2 
      1QN, UK.
FAU - Johnstone, Ricky W
AU  - Johnstone RW
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
AD  - Sir Peter MacCallum Department of Oncology, The University of Melbourne, East 
      Melbourne, Victoria 3002, Australia.
FAU - Dawson, Sarah-Jane
AU  - Dawson SJ
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
AD  - Sir Peter MacCallum Department of Oncology, The University of Melbourne, East 
      Melbourne, Victoria 3002, Australia.
FAU - Huntly, Brian J P
AU  - Huntly BJ
AD  - Department of Haematology, Cambridge Institute for Medical Research and Wellcome 
      Trust-MRC Stem Cell Institute, Cambridge CB2 0XY, UK.
FAU - Prinjha, Rab K
AU  - Prinjha RK
AD  - Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, 
      GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, 
      UK.
FAU - Papenfuss, Anthony T
AU  - Papenfuss AT
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
AD  - Sir Peter MacCallum Department of Oncology, The University of Melbourne, East 
      Melbourne, Victoria 3002, Australia.
AD  - Bioinformatics Division, The Walter &Eliza Hall Institute of Medical Research, 
      Parkville, Victoria 3052, Australia.
AD  - Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, 
      Australia.
FAU - Dawson, Mark A
AU  - Dawson MA
AD  - Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 
      3002, Australia.
AD  - Sir Peter MacCallum Department of Oncology, The University of Melbourne, East 
      Melbourne, Victoria 3002, Australia.
AD  - Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, 
      Victoria 3002, Australia.
LA  - eng
SI  - GEO/GSE63683
GR  - 14-1069/AICR_/Worldwide Cancer Research/United Kingdom
GR  - K08 CA160647/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - 17001/CRUK_/Cancer Research UK/United Kingdom
GR  - 10827/CRUK_/Cancer Research UK/United Kingdom
GR  - MR/M010392/1/MRC_/Medical Research Council/United Kingdom
GR  - 97922/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150914
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 ((+)-JQ1 compound)
RN  - 0 (Azepines)
RN  - 0 (BRD4 protein, human)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Chromatin)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Triazoles)
RN  - 0 (beta Catenin)
RN  - 12794-10-4 (Benzodiazepines)
RN  - 5QIO6SRZ2R (molibresib)
SB  - IM
MH  - Animals
MH  - Azepines/pharmacology
MH  - Benzodiazepines/*pharmacology
MH  - Cell Cycle Proteins
MH  - Cell Line, Tumor
MH  - Cells, Cultured
MH  - Chromatin/metabolism
MH  - Clone Cells/drug effects/metabolism/pathology
MH  - Drug Resistance, Neoplasm/*drug effects/genetics
MH  - Epigenesis, Genetic
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Genes, myc/genetics
MH  - Hematopoietic Stem Cells/cytology/drug effects/metabolism
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*drug therapy/genetics/*metabolism/pathology
MH  - Mice
MH  - Molecular Targeted Therapy
MH  - Neoplastic Stem Cells/*drug effects/metabolism/*pathology
MH  - Nuclear Proteins/*antagonists & inhibitors/metabolism
MH  - Transcription Factors/*antagonists & inhibitors/metabolism
MH  - Transcription, Genetic/drug effects
MH  - Triazoles/pharmacology
MH  - Wnt Signaling Pathway/drug effects
MH  - beta Catenin/metabolism
PMC - PMC6069604
MID - NIHMS982369
EDAT- 2015/09/15 06:00
MHDA- 2015/10/20 06:00
PMCR- 2018/08/01
CRDT- 2015/09/15 06:00
PHST- 2014/11/04 00:00 [received]
PHST- 2015/07/03 00:00 [accepted]
PHST- 2015/09/15 06:00 [entrez]
PHST- 2015/09/15 06:00 [pubmed]
PHST- 2015/10/20 06:00 [medline]
PHST- 2018/08/01 00:00 [pmc-release]
AID - nature14888 [pii]
AID - 10.1038/nature14888 [doi]
PST - ppublish
SO  - Nature. 2015 Sep 24;525(7570):538-42. doi: 10.1038/nature14888. Epub 2015 Sep 14.