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Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability

Author

Listed:
  • Jason P. Wray

    (UCL)

  • Elitza M. Deltcheva

    (UCL)

  • Charlotta Boiers

    (UCL
    Lund University)

  • Simon Е Richardson

    (UCL
    University of Cambridge
    Jeffrey Cheah Biomedical Centre)

  • Jyoti Bikram Chhetri

    (UCL)

  • John Brown

    (UCL)

  • Sladjana Gagrica

    (Cancer Research UK Cambridge Institute)

  • Yanping Guo

    (UCL)

  • Anuradha Illendula

    (University of Virginia)

  • Joost H. A. Martens

    (Radboud Institute for Molecular Life Sciences, Radboud University)

  • Hendrik G. Stunnenberg

    (Radboud Institute for Molecular Life Sciences, Radboud University)

  • John H. Bushweller

    (University of Virginia)

  • Rachael Nimmo

    (UCL
    Windrush Court, Transport Way)

  • Tariq Enver

    (UCL
    Lund University
    Lund Stem Cell Center, Lund University)

Abstract

The ETV6-RUNX1 onco-fusion arises in utero, initiating a clinically silent pre-leukemic state associated with the development of pediatric B-acute lymphoblastic leukemia (B-ALL). We characterize the ETV6-RUNX1 regulome by integrating chromatin immunoprecipitation- and RNA-sequencing and show that ETV6-RUNX1 functions primarily through competition for RUNX1 binding sites and transcriptional repression. In pre-leukemia, this results in ETV6-RUNX1 antagonization of cell cycle regulation by RUNX1 as evidenced by mass cytometry analysis of B-lineage cells derived from ETV6-RUNX1 knock-in human pluripotent stem cells. In frank leukemia, knockdown of RUNX1 or its co-factor CBFβ results in cell death suggesting sustained requirement for RUNX1 activity which is recapitulated by chemical perturbation using an allosteric CBFβ-inhibitor. Strikingly, we show that RUNX1 addiction extends to other genetic subtypes of pediatric B-ALL and also adult disease. Importantly, inhibition of RUNX1 activity spares normal hematopoiesis. Our results suggest that chemical intervention in the RUNX1 program may provide a therapeutic opportunity in ALL.

Suggested Citation

  • Jason P. Wray & Elitza M. Deltcheva & Charlotta Boiers & Simon Е Richardson & Jyoti Bikram Chhetri & John Brown & Sladjana Gagrica & Yanping Guo & Anuradha Illendula & Joost H. A. Martens & Hendrik G., 2022. "Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34653-3
    DOI: 10.1038/s41467-022-34653-3
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    References listed on IDEAS

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