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Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia

Author

Listed:
  • Quentin Van Thillo

    (KU Leuven
    Center for Cancer Biology, VIB
    Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven)

  • Jolien De Bie

    (KU Leuven
    Center for Cancer Biology, VIB
    Center for Human Genetics, UZ Leuven)

  • Janith A. Seneviratne

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney)

  • Sofie Demeyer

    (KU Leuven
    Center for Cancer Biology, VIB
    Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven)

  • Sofia Omari

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney)

  • Anushree Balachandran

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney)

  • Vicki Zhai

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney)

  • Wai L. Tam

    (Technology Innovation Lab, VIB)

  • Bram Sweron

    (KU Leuven
    Center for Cancer Biology, VIB)

  • Ellen Geerdens

    (KU Leuven
    Center for Cancer Biology, VIB
    Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven)

  • Olga Gielen

    (KU Leuven
    Center for Cancer Biology, VIB)

  • Sarah Provost

    (KU Leuven
    Center for Cancer Biology, VIB)

  • Heidi Segers

    (Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven
    KU Leuven
    UZ Leuven)

  • Nancy Boeckx

    (KU Leuven
    UZ Leuven)

  • Glenn M. Marshall

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney
    Kids Cancer Centre, Sydney Children’s Hospital)

  • Belamy B. Cheung

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney)

  • Kiyotaka Isobe

    (Kyoto University)

  • Itaru Kato

    (Kyoto University)

  • Junko Takita

    (Kyoto University)

  • Timothy G. Amos

    (Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research)

  • Ira W. Deveson

    (Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research
    St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney)

  • Hannah McCalmont

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney)

  • Richard B. Lock

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney)

  • Ethan P. Oxley

    (Australian Centre for Blood Diseases, Monash University)

  • Maximilian M. Garwood

    (Australian Centre for Blood Diseases, Monash University)

  • Ross A. Dickins

    (Australian Centre for Blood Diseases, Monash University)

  • Anne Uyttebroeck

    (Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven
    KU Leuven
    UZ Leuven)

  • Daniel R. Carter

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney
    School of Biomedical Engineering, University of Technology)

  • Jan Cools

    (KU Leuven
    Center for Cancer Biology, VIB
    Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven)

  • Charles E. de Bock

    (Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
    School of Women’s and Children’s Health, UNSW Sydney)

Abstract

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.

Suggested Citation

  • Quentin Van Thillo & Jolien De Bie & Janith A. Seneviratne & Sofie Demeyer & Sofia Omari & Anushree Balachandran & Vicki Zhai & Wai L. Tam & Bram Sweron & Ellen Geerdens & Olga Gielen & Sarah Provost , 2021. "Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24442-9
    DOI: 10.1038/s41467-021-24442-9
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