BET inhibitor resistance emerges from leukaemia stem cells
Open accessAbstract
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/β-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.
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- Authors
- Fong, C. Y., Gilan, O., Lam, E. Y. N., Rubin, A. F., Ftouni, S., Tyler, D., Stanley, K., Sinha, D., Yeh, P., Morison, J., Giotopoulos, G., Lugo, D., Jeffrey, P., Lee, S. C.-W., Carpenter, C., Gregory, R., Ramsay, R. G., Lane, S. W., Abdel-Wahab, O., Kouzarides, T., Johnstone, R. W., Dawson, S.-J., Huntly, B. J. P., Prinjha, R. K., Papenfuss, A. T., & Dawson, M. A.
- Affiliations
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- Memorial Sloan Kettering Cancer Center (US)
- GlaxoSmithKline (United States) (US)
- The University of Queensland (AU)
- The Gurdon Institute (GB)
- Corresponding author
- Dawson, Mark A.
- ORCID
- Fong, Chun Yew
- Gilan, Omer
- Lam, Enid Y. N.
- Rubin, Alan F.
- Ftouni, Sarah
- Yeh, Paul
- Giotopoulos, George
- Lugo, Dave
- Lee, Stanley Chun-Wei
- Carpenter, Christopher
- Gregory, Richard
- Ramsay, Robert G.
- Lane, Steven W.
- Abdel-Wahab, Omar
- Kouzarides, Tony
- Johnstone, Ricky W.
- Dawson, Sarah-Jane
- Huntly, Brian J. P.
- Prinjha, Rab K.
- Papenfuss, Anthony T.
- Dawson, Mark A.
- Venue
- Nature
- Published
- 2015-09
- Volume
- 525
- Issue
- 7570
- Pages
- 538-542
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6069604
- OpenAlex
- W2162520885
- Cited by
- 545
- References
- 44
- Citations by year
- 2026: 23 · 2025: 38 · 2024: 33 · 2023: 48 · 2022: 40 · 2021: 61 · 2020: 59 · 2019: 56 · 2018: 57 · 2017: 70 · 2016: 52 · 2015: 7
- FWCI
- 26.91
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust (97922, 092096)
- Cancer Research UK (10827, 17001)
- Medical Research Council (MR/M010392/1)
- National Cancer Institute (K08CA160647, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- BET inhibitors, drug resistance, leukemia stem cells, MLL-AF9, Wnt/β-catenin signaling, BRD4, polycomb repressive complex 2, acute myeloid leukemia, JQ1, c-Myc, chromatin acetylation, hematopoietic stem cells, single-cell clones, cross-resistance, transcriptional regulation
- MeSH terms
- Bromodomain Containing Proteins, Animals, Azepines, Benzodiazepines, Cells, Cultured, Chromatin, Clone Cells, Hematopoietic Stem Cells, Humans, Nuclear Proteins, Transcription Factors, Transcription, Genetic, Triazoles, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, Genes, myc, Cell Cycle Proteins, Drug Resistance, Neoplasm, Epigenesis, Genetic, Cell Line, Tumor, beta Catenin, Mice, Molecular Targeted Therapy, Wnt Signaling Pathway
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