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 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 NFE2L2 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 NFE2L2 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 NFE2L2 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.

Automated summary

The standard-of-care treatment for T-cell acute lymphoblastic leukaemia (T-ALL) achieves reasonable response rates, but relapsed or treatment-resistant patients have poor outcomes. This study explores the potential of NRF2 activation as a prognostic biomarker in T-ALL. Through analysis of transcriptomic, genomic, and clinical data, high NFE2L2 levels were found to be associated with shorter overall survival in T-ALL patients. The PI3K-AKT-mTOR pathway plays a role in the oncogenic signaling induced by NRF2 in T-ALL. High NFE2L2 levels are also associated with drug resistance in T-ALL, possibly due to NRF2-induced glutathione biosynthesis. These findings suggest that NFE2L2 levels could be a predictive biomarker for poor treatment response in T-ALL patients, offering insights for improved patient stratification and targeted therapies.