Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D)

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.

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FIG: Identification and characterization of the TCF7-SPI1fusion in patient X09 with T-cell acute lymphoblastic leukemia: a Left panel: flow cytometry staining of the X09 patient sample for cyCD3, CD1a, CD4, CD8, CD117, CD2, CD7, HLA-DR. Right panel: Circos plot showing the translocation between chromosomes 5 and 11 in the X09 patient. Additional mutations are shown with their respective chromosomal location. b Scheme of the t(5;11) translocation between TCF7 and SPI1. The breakpoints are located at TCF7 intron 4-5 (Chr. 5) and SPI1 intron 2–3 (Chr. 11). c Long read nanopore sequencing confirming the translocation with the resulting GridION reads shown schematically alongside Sanger sequencing confirmation of the breakpoint region. d Schematic representation of the resulting TCF1-PU.1 (TCF7-SPI1) fusion protein. The different domains are shown. CTNNB1: β-catenin binding domain; TAD: trans-activating domain; HMG: high mobility group box.

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 ofSPI1 targets. Together, our results reveal an example where TCF7-SPI1leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.

Van Thillo, Q., De Bie, J., Seneviratne, J.A. et al. Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia. Nat Commun 12, 4164 (2021). https://doi.org/10.1038/s41467-021-24442-9

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