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Cited by 57Acute Myeloid Leukemia ResearchAcute Lymphoblastic Leukemia researchProtein Degradation and Inhibitors

Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

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Booth, Christopher A.G., Barkas, Nikolaos, Neo, Wen Hao, Boukarabila, Hanane, Soilleux, Elizabeth J., Giotopoulos, George, Farnoud, Noushin, Giustacchini, Alice +12 more·2018·Cancer Cell
DOI 10.1016/j.ccell.2018.01.006
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Abstract

Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition in vitro and in vivo, which reverses aberrant gene expression induced by Ezh2 inactivation.

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  • The data are compatible with a fitness advantage of monosomy 7 cells, a recurrent event in TP53-sAML, driven by activation of signaling pathways that may relate to deletion of chromosome 7 genes such as EZH2.

    “Together, these data are compatible with a fitness advantage of monosomy 7 cells, a recurrent event in TP53-sAML (Extended Data Fig. 1b,c), driven by activation of signaling pathways that may relate to deletion of chromosome 7 genes such as EZH2 (ref. 20).”

    From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [20]

    The Discussion (page unavailable) reports that Ezh2 loss increased expression of oncogenic Flt3-ITD signaling in a mouse model of early thymic progenitor leukemia, supporting the proposed link between EZH2 loss and signaling. It does not establish that chromosome 7 deletion activates signaling or gives monosomy 7 cells a fitness advantage in TP53-sAML; the paper cautions that its findings cannot be extrapolated to other contexts without validation. (LLM, conf=0.86)

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Authors
Booth, C. A. G., Barkas, N., Neo, W. H., Boukarabila, H., Soilleux, E. J., Giotopoulos, G., Farnoud, N., Giustacchini, A., Ashley, N., Carrelha, J., Jamieson, L., Atkinson, D., Bouriez-Jones, T., Prinjha, R. K., Milne, T. A., Teachey, D. T., Papaemmanuil, E., Huntly, B. J. P., Jacobsen, S. E. W., & Mead, A. J.
Affiliations
  • University of Oxford (GB)
  • University of Cambridge (GB)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • Memorial Sloan Kettering Cancer Center (US)
  • GlaxoSmithKline (United Kingdom) (GB)
  • Children's Hospital of Philadelphia (US)
  • Karolinska University Hospital (SE)
  • Churchill Hospital (GB)
Corresponding author
  • Jacobsen, Sten Eirik W.
  • Mead, Adam J.
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2018-02
Volume
33
Issue
2
Pages
274-291.e8
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccell.2018.01.006
OpenAlex
W2787228004
Cited by
57
References
6
Citations by year
2025: 4 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 12 · 2020: 12 · 2019: 8 · 2018: 5
FWCI
6.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
  • Apollo
Funders
  • Kay Kendall Leukaemia Fund (KKL811)
  • Medical Research Council (MR/L006340/1, MC_UU_12009/5, MR/M00919X/1, MC_UU_12009)
  • Swedish Research Council
  • NIHR (131/030, 101/517)
  • EPA (CF182, CF170)
  • WIMM (G0902418, MC_UU_12025)
  • Oxford-Wellcome Trust
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords
EZH2 mutation, RUNX1 mutation, Ras signaling, FLT3-ITD, BET inhibition, transcriptional dysregulation, mouse model, treatment resistance
MeSH terms
Enhancer of Zeste Homolog 2 Protein, Animals, Mutation, Stem Cells, Signal Transduction, Leukemia, Myeloid, Acute, Gene Expression Regulation, Leukemic, Mice, Knockout, Myeloid Cells, Core Binding Factor Alpha 2 Subunit

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