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

Authors :
Tosello V
Bongiovanni D
Liu J
Pan Q
Yan KK
Saccomani V
Van Trimpont M
Pizzi M
Mazzoni M
Dei Tos AP
Amadori A
Zanovello P
Van Vlierberghe P
Yu J
Piovan E
Source :
Leukemia [Leukemia] 2021 Apr; Vol. 35 (4), pp. 984-1000. Date of Electronic Publication: 2020 Jul 30.
Publication Year :
2021

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.

Details

Language :
English
ISSN :
1476-5551
Volume :
35
Issue :
4
Database :
MEDLINE
Journal :
Leukemia
Publication Type :
Academic Journal
Accession number :
32733009
Full Text :
https://doi.org/10.1038/s41375-020-0999-2