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. AmosIra W. Deveson, Hannah McCalmont, Richard B. Lock, Ethan P. Oxley, Maximilian M. Garwood, Ross A. Dickins, Anne Uyttebroeck, Daniel R. Carter, Jan Cools, Charles E. de Bock

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10 Citations (Scopus)


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.

Original languageEnglish
Article number4164
Number of pages15
JournalNature Communications
Issue number1
Publication statusPublished - Dec 2021

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