Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination
- Author
- Valeria Tosello, Deborah Bongiovanni, Jingjing Liu, Qingfei Pan, Koon-kiu Yan, Valentina Saccomani, Maaike Van Trimpont (UGent) , Marco Pizzi, Martina Mazzoni, Angelo Paolo Dei Tos, Alberto Amadori, Paola Zanovello, Pieter Van Vlierberghe (UGent) , Jiyang Yu and Erich Piovan
- Organization
- 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.
- Keywords
- Anesthesiology and Pain Medicine, Cancer Research, Hematology, HEDGEHOG PATHWAY, EXPRESSION, CANCER, CXCR4, ACTIVATION, REGULATOR, MECHANISM, KINASES, HES1, AKT
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8700765
- MLA
- Tosello, Valeria, et al. “Cross-Talk between GLI Transcription Factors and FOXC1 Promotes T-Cell Acute Lymphoblastic Leukemia Dissemination.” LEUKEMIA, vol. 35, no. 4, 2021, pp. 984–1000, doi:10.1038/s41375-020-0999-2.
- APA
- Tosello, V., Bongiovanni, D., Liu, J., Pan, Q., Yan, K., Saccomani, V., … Piovan, E. (2021). Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination. LEUKEMIA, 35(4), 984–1000. https://doi.org/10.1038/s41375-020-0999-2
- Chicago author-date
- Tosello, Valeria, Deborah Bongiovanni, Jingjing Liu, Qingfei Pan, Koon-kiu Yan, Valentina Saccomani, Maaike Van Trimpont, et al. 2021. “Cross-Talk between GLI Transcription Factors and FOXC1 Promotes T-Cell Acute Lymphoblastic Leukemia Dissemination.” LEUKEMIA 35 (4): 984–1000. https://doi.org/10.1038/s41375-020-0999-2.
- Chicago author-date (all authors)
- Tosello, Valeria, 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, and Erich Piovan. 2021. “Cross-Talk between GLI Transcription Factors and FOXC1 Promotes T-Cell Acute Lymphoblastic Leukemia Dissemination.” LEUKEMIA 35 (4): 984–1000. doi:10.1038/s41375-020-0999-2.
- Vancouver
- 1.Tosello V, Bongiovanni D, Liu J, Pan Q, Yan K, Saccomani V, et al. Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination. LEUKEMIA. 2021;35(4):984–1000.
- IEEE
- [1]V. Tosello et al., “Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination,” LEUKEMIA, vol. 35, no. 4, pp. 984–1000, 2021.
@article{8700765, 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.}}, author = {{Tosello, Valeria and Bongiovanni, Deborah and Liu, Jingjing and Pan, Qingfei and Yan, Koon-kiu and Saccomani, Valentina and Van Trimpont, Maaike and Pizzi, Marco and Mazzoni, Martina and Dei Tos, Angelo Paolo and Amadori, Alberto and Zanovello, Paola and Van Vlierberghe, Pieter and Yu, Jiyang and Piovan, Erich}}, issn = {{0887-6924}}, journal = {{LEUKEMIA}}, keywords = {{Anesthesiology and Pain Medicine,Cancer Research,Hematology,HEDGEHOG PATHWAY,EXPRESSION,CANCER,CXCR4,ACTIVATION,REGULATOR,MECHANISM,KINASES,HES1,AKT}}, language = {{eng}}, number = {{4}}, pages = {{984--1000}}, title = {{Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination}}, url = {{http://doi.org/10.1038/s41375-020-0999-2}}, volume = {{35}}, year = {{2021}}, }
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