Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia.
Quentin Van ThilloJolien De BieJanith A SeneviratneSofie DemeyerSofia A OmariAnushree BalachandranVicki ZhaiWai L TamBram SweronEllen GeerdensOlga GielenSarah ProvostHeidi SegersNancy BoeckxGlenn M MarshallBelamy B CheungKiyotaka IsobeItaru KatoJunko TakitaTimothy G AmosIra W DevesonHannah McCalmontRichard B LockEthan P OxleyMaximilian M GarwoodRoss A DickinsAnne UyttebroeckDaniel R CarterJan CoolsCharles E de BockPublished in: Nature communications (2021)
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.
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