AKR1C enzymes sustain therapy resistance in paediatric T-ALL

Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T- ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T- ALLmight involve aldo-keto reductase1C (AKR1C) enzymes as previously reported for solid tumors. Expression of NRF2-AKR1C signaling components has been analysed in paediatric T- ALLsamples endowed with different treatment outcomes as well as in patient-derived xenografts of T- ALL. The effects of AKR1C enzyme modulationhas been investigated in T- ALLcell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches. We show that T- ALLcells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T- ALLcells to VCR. Finally, we show that T- ALLchemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T- ALLcombination treatment. Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T- ALL, posing AKR1C1-3 as potential targets for combination treatments during T- ALLtherapy.