Abstract
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.
Highlights
Peripheral blood cells from patient X09, a 6-year old boy newly diagnosed with an immature CD4/CD8 double negative TALL, underwent whole-genome and RNA sequencing, revealing a translocation between chromosomes 5 and 11 and co-occurring mutations in NRAS, NOTCH1, Krüppel-like factor 9 (KLF9), Cyclindependent kinase inhibitor 2A (CDKN2A), Sidekick cell adhesion molecule 1 (SDK1), T-cell receptor gamma (TRG), and transducin-like 1 X-linked receptor 1 (TBL1XR1) (Fig. 1a)
In 2017, Seki et al described a distinct subset of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases with dismal prognosis, characterized by an aberrant expression of Spi-1 Proto-Oncogene (SPI1) fusion genes
Even though Transcription factor 7 (TCF7) appeared to be a stronger activator of PU.[1] than STMN1, the authors were unable to induce T-cell leukemia in a mouse model by constitutively expressing TCF7-SPI1 on its own[9]
Summary
While SPI1 (PU.1) is an important transcription factor in all hematopoietic cells, TCF7 (located on the short arm of chromosome 5) encodes TCF1, a T-cell specific transcriptional activator that is highly expressed in the earliest thymic progenitors and controls chromatin accessibility of T-cell regulatory elements[10,11]. To evaluate the role of SPI1 fusion genes in T-ALL, Seki et al expressed distinct fusion transcripts in mouse stem/progenitor cells and documented an increased T-cell proliferation and a maturation block at the DN3 stage upon SPI1 or SPI1 fusion expression. Whilst TCF7-SPI1 fusions are insufficient for frank T-cell leukemia development, these clinical cases are often coincident with NRAS mutations suggesting the potential for oncogenic cooperation. We show that TCF7-SPI1 fusions and the NRAS(G12D) activating mutation cooperate to form an immature T-ALL in vivo that is absent when each is expressed alone.
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