Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic Leukaemia
The standard-of-care treatment of T-cell acute lymphoblastic leukaemia (T-ALL) with chemotherapy usually achieves reasonable rates of initial complete response. However, patients who relapse or do not respond to conventional therapy show dismal outcomes, with cure rates below 10% and limited therape...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/12/10350 |
| _version_ | 1797594309300584448 |
|---|---|
| author | María Villa-Morales Laura Pérez-Gómez Eduardo Pérez-Gómez Pilar López-Nieva Pablo Fernández-Navarro Javier Santos |
| author_facet | María Villa-Morales Laura Pérez-Gómez Eduardo Pérez-Gómez Pilar López-Nieva Pablo Fernández-Navarro Javier Santos |
| author_sort | María Villa-Morales |
| collection | DOAJ |
| description | The standard-of-care treatment of T-cell acute lymphoblastic leukaemia (T-ALL) with chemotherapy usually achieves reasonable rates of initial complete response. However, patients who relapse or do not respond to conventional therapy show dismal outcomes, with cure rates below 10% and limited therapeutic options. To ameliorate the clinical management of these patients, it is urgent to identify biomarkers able to predict their outcomes. In this work, we investigate whether NRF2 activation constitutes a biomarker with prognostic value in T-ALL. Using transcriptomic, genomic, and clinical data, we found that T-ALL patients with high <i>NFE2L2</i> levels had shorter overall survival. Our results demonstrate that the PI3K-AKT-mTOR pathway is involved in the oncogenic signalling induced by NRF2 in T-ALL. Furthermore, T-ALL patients with high <i>NFE2L2</i> levels displayed genetic programs of drug resistance that may be provided by NRF2-induced biosynthesis of glutathione. Altogether, our results indicate that high levels of <i>NFE2L2</i> may be a predictive biomarker of poor treatment response in T-ALL patients, which would explain the poor prognosis associated with these patients. This enhanced understanding of NRF2 biology in T-ALL may allow a more refined stratification of patients and the proposal of targeted therapies, with the ultimate goal of improving the outcome of relapsed/refractory T-ALL patients. |
| first_indexed | 2024-03-11T02:20:50Z |
| format | Article |
| id | doaj.art-e568ebac34244decb41903ee781a04ed |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T02:20:50Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e568ebac34244decb41903ee781a04ed2023-11-18T10:52:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-0124121035010.3390/ijms241210350Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic LeukaemiaMaría Villa-Morales0Laura Pérez-Gómez1Eduardo Pérez-Gómez2Pilar López-Nieva3Pablo Fernández-Navarro4Javier Santos5Department of Biology, Universidad Autónoma de Madrid, 28049 Madrid, SpainDepartment of Biology, Universidad Autónoma de Madrid, 28049 Madrid, SpainDepartamento de Bioquímica y Biología Molecular, Universidad Complutense de Madrid, 28040 Madrid, SpainDepartment of Biology, Universidad Autónoma de Madrid, 28049 Madrid, SpainUnit of Cancer and Environmental Epidemiology, Centro Nacional de Epidemiología, Instituto de Salud Carlos III, 28029 Madrid, SpainDepartment of Biology, Universidad Autónoma de Madrid, 28049 Madrid, SpainThe standard-of-care treatment of T-cell acute lymphoblastic leukaemia (T-ALL) with chemotherapy usually achieves reasonable rates of initial complete response. However, patients who relapse or do not respond to conventional therapy show dismal outcomes, with cure rates below 10% and limited therapeutic options. To ameliorate the clinical management of these patients, it is urgent to identify biomarkers able to predict their outcomes. In this work, we investigate whether NRF2 activation constitutes a biomarker with prognostic value in T-ALL. Using transcriptomic, genomic, and clinical data, we found that T-ALL patients with high <i>NFE2L2</i> levels had shorter overall survival. Our results demonstrate that the PI3K-AKT-mTOR pathway is involved in the oncogenic signalling induced by NRF2 in T-ALL. Furthermore, T-ALL patients with high <i>NFE2L2</i> levels displayed genetic programs of drug resistance that may be provided by NRF2-induced biosynthesis of glutathione. Altogether, our results indicate that high levels of <i>NFE2L2</i> may be a predictive biomarker of poor treatment response in T-ALL patients, which would explain the poor prognosis associated with these patients. This enhanced understanding of NRF2 biology in T-ALL may allow a more refined stratification of patients and the proposal of targeted therapies, with the ultimate goal of improving the outcome of relapsed/refractory T-ALL patients.https://www.mdpi.com/1422-0067/24/12/10350T-cell acute lymphoblastic leukaemia (T-ALL)NRF2 (nuclear factor erythroid 2-related factor 2)prognostic biomarker |
| spellingShingle | María Villa-Morales Laura Pérez-Gómez Eduardo Pérez-Gómez Pilar López-Nieva Pablo Fernández-Navarro Javier Santos Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic Leukaemia International Journal of Molecular Sciences T-cell acute lymphoblastic leukaemia (T-ALL) NRF2 (nuclear factor erythroid 2-related factor 2) prognostic biomarker |
| title | Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic Leukaemia |
| title_full | Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic Leukaemia |
| title_fullStr | Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic Leukaemia |
| title_full_unstemmed | Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic Leukaemia |
| title_short | Identification of NRF2 Activation as a Prognostic Biomarker in T-Cell Acute Lymphoblastic Leukaemia |
| title_sort | identification of nrf2 activation as a prognostic biomarker in t cell acute lymphoblastic leukaemia |
| topic | T-cell acute lymphoblastic leukaemia (T-ALL) NRF2 (nuclear factor erythroid 2-related factor 2) prognostic biomarker |
| url | https://www.mdpi.com/1422-0067/24/12/10350 |
| work_keys_str_mv | AT mariavillamorales identificationofnrf2activationasaprognosticbiomarkerintcellacutelymphoblasticleukaemia AT lauraperezgomez identificationofnrf2activationasaprognosticbiomarkerintcellacutelymphoblasticleukaemia AT eduardoperezgomez identificationofnrf2activationasaprognosticbiomarkerintcellacutelymphoblasticleukaemia AT pilarlopeznieva identificationofnrf2activationasaprognosticbiomarkerintcellacutelymphoblasticleukaemia AT pablofernandeznavarro identificationofnrf2activationasaprognosticbiomarkerintcellacutelymphoblasticleukaemia AT javiersantos identificationofnrf2activationasaprognosticbiomarkerintcellacutelymphoblasticleukaemia |