TY - JOUR
T1 - Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination
AU - Tosello, Valeria
AU - Bongiovanni, Deborah
AU - Liu, Jingjing
AU - Pan, Qingfei
AU - Yan, Koon kiu
AU - Saccomani, Valentina
AU - Van Trimpont, Maaike
AU - Pizzi, Marco
AU - Mazzoni, Martina
AU - Dei Tos, Angelo Paolo
AU - Amadori, Alberto
AU - Zanovello, Paola
AU - Van Vlierberghe, Pieter
AU - Yu, Jiyang
AU - Piovan, Erich
N1 - Funding Information:
Funding 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.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7/30
Y1 - 2020/7/30
N2 - 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.
AB - 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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U2 - 10.1038/s41375-020-0999-2
DO - 10.1038/s41375-020-0999-2
M3 - Article
AN - SCOPUS:85088792902
JO - Leukemia
JF - Leukemia
SN - 0887-6924
ER -