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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.

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