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


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 beta-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/beta-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/beta-catenin interaction.

Type Journal
ISBN 2041-1723 (Electronic) 2041-1723 (Linking)
Authors Van Thillo, Q.; De Bie, J.; Seneviratne, J. A.; Demeyer, S.; Omari, S.; Balachandran, A.; Zhai, V.; Tam, W. L.; Sweron, B.; Geerdens, E.; Gielen, O.; Provost, S.; Segers, H.; Boeckx, N.; Marshall, G. M.; Cheung, B. B.; Isobe, K.; Kato, I.; Takita, J.; Amos, T. G.; Deveson, I. W.; McCalmont, H.; Lock, R. B.; Oxley, E. P.; Garwood, M. M.; Dickins, R. A.; Uyttebroeck, A.; Carter, D. R.; Cools, J.; de Bock, C. E.
Publisher Name Nature Communications
Published Date 2021-07-31
Published Volume 12
Published Issue 1
Published Pages 4164
Status Published in-print
DOI 10.1038/s41467-021-24442-9
URL link to publisher's version