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

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, Heidi Segers, Nancy Boeckx, Glenn M. Marshall, Belamy B. Cheung, Kiyotaka Isobe, Itaru Kato, Junko Takita, Timothy G. Amos, Ira W. Deveson, Hannah McCalmont, Richard B. Lock, Ethan P. Oxley, Maximilian M. Garwood, Ross A. Dickins, Anne Uyttebroeck, Daniel R. Carter, Jan Cools () and Charles E. de Bock ()
Additional contact information
Quentin Van Thillo: KU Leuven
Jolien De Bie: KU Leuven
Janith A. Seneviratne: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
Sofie Demeyer: KU Leuven
Sofia Omari: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
Anushree Balachandran: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
Vicki Zhai: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
Wai L. Tam: Technology Innovation Lab, VIB
Bram Sweron: KU Leuven
Ellen Geerdens: KU Leuven
Olga Gielen: KU Leuven
Sarah Provost: KU Leuven
Heidi Segers: Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven
Nancy Boeckx: KU Leuven
Glenn M. Marshall: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
Belamy B. Cheung: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
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
Hannah McCalmont: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
Richard B. Lock: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
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
Daniel R. Carter: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre
Jan Cools: KU Leuven
Charles E. de Bock: Children’s Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24442-9

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