Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination

Valeria Tosello, Deborah Bongiovanni, Jingjing Liu, Qingfei Pan, Koon kiu Yan, Valentina Saccomani, Maaike Van Trimpont, Marco Pizzi, Martina Mazzoni, Angelo Paolo Dei Tos, Alberto Amadori, Paola Zanovello, Pieter Van Vlierberghe, Jiyang Yu, Erich Piovan

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Number of pages17
JournalLeukemia
DOIs
Publication statusE-pub ahead of print - Jul 30 2020

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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