T-cell acute lymphoblastic leukemia (T-ALL) is a highly malignant pediatric leukemia, where few therapeutic options are available for patients which relapse. We find that therapeutic targeting of GLI transcription factors by GANT-61 is particularly effective against NOTCH1 unmutated T-ALL cells. Investigation of the functional role of GLI1 disclosed that it contributes to T-ALL cell proliferation, survival, and dissemination through the modulation of AKT and CXCR4 signaling pathways. Decreased CXCR4 signaling following GLI1 inactivation was found to be prevalently due to post-transcriptional mechanisms including altered serine 339 CXCR4 phosphorylation and cortactin levels. We also identify a novel cross-talk between GLI transcription factors and FOXC1. Indeed, GLI factors can activate the expression of FOXC1 which is able to stabilize GLI1/2 protein levels through attenuation of their ubiquitination. Further, we find that prolonged GLI1 deficiency has a double-edged role in T-ALL progression favoring disease dissemination through the activation of a putative AKT/FOXC1/GLI2 axis. These findings have clinical significance as T-ALL patients with extensive central nervous system dissemination show low GLI1 transcript levels. Further, T-ALL patients having a GLI2-based Hedgehog activation signature are associated with poor survival. Together, these findings support a rationale for targeting the FOXC1/AKT axis to prevent GLI-dependent oncogenic Hedgehog signaling.
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We are grateful to Jon Aster for the MigR1-NOTCH1 L1601PΔP vector, Sonia Minuzzo and Marica Pinazza for providing T-ALL xenografts, Silvia Dalla Santa and Elena Laura Mazzoldi for cell sorting, Elena Masiero and Vito Barbieri for technical assistance. We are grateful to Xiaojiang Cui for generously donating the pBABE-puro-FOXC1 vector. We are particularly grateful to Gloria Milani for performing gene expression profiling on PDX samples. We are grateful to Stacey Odgen for sharing GLI antibodies.
This work was supported by the Italian Foundation for Cancer Research (Fondazione AIRC) grants to EP (IG2018#22233) and PZ (IG2013#14256); Progetto di Ricerca di Ateneo (SID19_01; Università di Padova) to EP Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) Ex 60% to EP; Istituto Oncologico Veneto 5×1000 fund to EP. There are no conflicts of interest to declare.
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Tosello, V., Bongiovanni, D., Liu, J. et al. Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination. Leukemia (2020). https://doi.org/10.1038/s41375-020-0999-2